Fused amino pyridine as hsp90 inhibitors

ABSTRACT

The present invention relates to HSP90 inhibitors containing fused amino pyridine core that are useful as inhibitors of HSP90 and their use in the treatment of HSP90 related diseases and disorders such as cancer, an autoimmune disease, or a neurodegenerative disease.

RELATED APPLICATIONS

This application is a continuation of application Ser. No. 14/681,310filed on Apr. 8, 2015, which is a continuation of U.S. application Ser.No. 14/054,273, filed Oct. 15, 2013 (now U.S. Pat. No. 9,040,556), whichis a continuation of U.S. application Ser. No. 13/424,780 (now U.S. Pat.No. 8,586,605), filed Mar. 20, 2012, which is a continuation of U.S.application Ser. No. 12/045,509 (now U.S. Pat. No. 8,324,240), filedMar. 10, 2008, which claims the benefit of U.S. Provisional ApplicationNo. 60/895,921, filed on Mar. 20, 2007 and U.S. Provisional ApplicationNo. 61/015,288, filed on Dec. 20, 2007. The entire teachings of theabove applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

HSP90s are ubiquitous chaperone proteins that are involved in properprotein folding and stabilization of a wide range of proteins, includingkey proteins involved in signal transduction, cell cycle control andtranscriptional regulation. Researchers have reported that HSP90chaperone proteins are associated with important signaling proteins,such as steroid hormone receptors and protein kinases, including, e.g.,Raf-1, EGFR, v-Src family kinases, Cdk4, and ErbB-2, many of which areoverexpressed or mutated in various cancers (Buchner J. TIBS, 1999, 24,136 141; Stepanova, L. et al. Genes Dev. 1996, 10, 1491 502; Dai, K. etal. J. Biol. Chem. 1996, 271, 22030-4). Studies further indicate thatcertain co-chaperones, e.g., HSP70, p60/Hop/Sti1, Hip, Bag1,HSP40/Hdj2/Hsj1, immunophilins, p23, and p50, may assist HSP90 in itsfunction (Caplan, A. Trends in Cell Biol. 1999, 9, 262 68).

HSP90 has been shown by mutational analysis to be necessary for thesurvival of normal eukaryotic cells. However, HSP90 is over expressed inmany tumor types indicating that it may play a significant role in thesurvival of cancer cells and that cancer cells may be more sensitive toinhibition of HSP90 than normal cells. For example, cancer cellstypically have a large number of mutated and overexpressed oncoproteinsthat are dependent on HSP90 for folding. In addition, because theenvironment of a tumor is typically hostile due to hypoxia, nutrientdeprivation, acidosis, etc., tumor cells may be especially dependent onHSP90 for survival. Moreover, inhibition of HSP90 causes simultaneousinhibition of a number of client oncoproteins, as well as hormonereceptors and transcription factors making it an attractive target foran anti-cancer agent. In fact, benzoquinone ansamycins, a family ofnatural products that inhibit HSP90, has shown evidence of therapeuticactivity in clinical trials. Several promising ansamycin related HSP90inhibitors are currently in clinical trial namely, 17-allylamino17-demethoxygeldanamycin (17-AAG),17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) andIPI-504. Another class of the HSP90 inhibitor is the synthetic smallmolecule purine-scaffold. Currently, many of the purine-scaffold HSP90inhibitors are showing positive preclinical results; with the frontrunner being CNF-2024, which is currently in phase 1 clinical trial.

Recent studies suggest that heat shock proteins (HSPs) play an importantrole in neurodegenerative disorders such as Parkinson's disease (PD),Alzheimer's disease (AD), amyotropic lateral sclerosis (ALS), Huntingtondisease (HD) (Luo, G-R. Int. J. Biol. Sci., 2007, 3(1), 20-26; Dickey,C., J. Clin. Invest., 2007, 117(3), p. 648-658). It has been shown thatmanipulation of HSPs, such as down regulation of HSP90 or up regulationof HSP70, affords beneficial effects in several neurodegenerativedisorders either by reducing protein aggregation or facilitating properfolding of proteins to restore their function.

Drugs targeting the protein HSP90 are quite new in cancer andneurodegenerative disease therapies. Research relating to HSP90 israpidly developing and therefore, the need for novel and activecompounds exists. As such, this invention relates to fused aminopyridine compounds useful as HSP90 inhibitors.

SUMMARY OF THE INVENTION

The present invention relates to HSP90 inhibitors containing fused aminopyridine core that are useful as inhibitors of HSP90 and their use inthe treatment of HSP90 related diseases and disorders such as cancer, anautoimmune disease, or a neurodegenerative disease.

Accordingly, the present invention provides a compound having thegeneral formula I:

or its geometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, prodrugs and solvates thereof,wherein

-   -   U is N or CH;    -   W is hydrogen, halogen, amino, hydroxy, thiol, alkyl,        substituted alkyl, substituted or unsubstituted alkoxy,        substituted or unsubstituted alkylamino, substituted or        unsubstituted dialkylamino, substituted or unsubstituted        alkylthio, substituted or unsubstituted alkylsulfonyl, CF₃, NO₂,        CN, N₃, sulfonyl, acyl, aryl, substituted aryl, heteroaryl,        substituted heteroaryl, heterocyclic, substituted heterocyclic,        cycloalkyl, or substituted cycloalkyl;    -   X is absent, O, S, S(O), S(O)₂, N(R₈), C(O), CF₂, C(R₈) or C₂-C₆        alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl in which one or more        methylene can be interrupted or terminated by O, S, SO, SO₂,        N(R₈), C(O), where R₈ is hydrogen, acyl, aliphatic or        substituted aliphatic;    -   Y is independently hydrogen, halogen, NO₂, CN, or lower alkyl;    -   Z is amino, substituted or unsubstituted alkylamino, substituted        or unsubstituted dialkylamino, substituted or unsubstituted        alkylcarbonylamino;    -   Q is aryl, substituted aryl, heteroaryl, substituted heteroaryl,        cycloalkyl, or heterocycloalkyl;    -   V is hydrogen, straight- or branched-, substituted or        unsubstituted alkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted alkynyl, which one or more        methylenes can be interrupted or terminated by O, S, S(O), SO₂,        N(R₈), C(O), substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heterocyclic; substituted or unsubstituted cycloalkyl; where R₈        is hydrogen, acyl, aliphatic or substituted aliphatic.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment of the compounds of the present invention arecompounds represented by formula (I) as illustrated above, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, prodrugs and solvates thereof.

In a second embodiment of the compounds of the present invention arecompounds represented by formula (II) as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, prodrugs and solvates thereof:

wherein X₂ and X₅ are independently CR₂₁ or N; R₂₁-R₂₃ are independentlyselected from the group consisting of hydrogen, halogen, amino,substituted amino, hydroxy, substituted hydroxy, thiol, substitutedthiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkylamino, substituted or unsubstituted dialkylamino,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkylsulfonyl, CF₃, NO₂, CN, N₃, substituted carbonyl, sulfonyl, acyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, cycloalkyl, or substitutedcycloalkyl; R₂₂ and R₂₃ can be taken together from the carbon to whichthey are attached to form a saturated or unsaturated fused 5-8 memberedcyclic ring optionally substituted with 0-3 heteroatom; M₁ is absent,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl or heteroaryl; M₂ isabsent, O, S, SO, SO₂, N(R₈), or C═O; M₃ is absent, C═O, O, S, SO, SO₂or N(R₈); M₄ is hydrogen, halogen, CN, N₃, hydroxy, substituted hydroxy,amino, substituted amino, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; and X, Y and Zare as previously defined.

In one example, X₂ and X₅ are independently CH or N; R₂₁-R₂₃ areindependently selected from the group consisting of hydrogen, halogen,amino, hydroxy, thiol, alkyl, substituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylamino,substituted or unsubstituted dialkylamino, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkylsulfonyl, CF₃, NO₂, CN, N₃,sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, orsubstituted cycloalkyl; R₂₂ and R₂₃ can be taken together from thecarbon to which they are attached to form a saturated or unsaturatedfused 5-8 membered cyclic ring optionally substituted with 0-3heteroatom; M₁ is absent, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,aryl or heteroaryl; M₂ is absent, O, S, SO, SO₂, N(R₈), or C═O; M₃ isabsent, C═O, O, S, SO, SO₂ or N(R₈); M₄ is hydrogen, halogen, CN, N₃,hydroxy, amino, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,cycloalkyl, heterocyclic, aryl or heteroaryl; and X, Y and Z are aspreviously defined.

In a third embodiment of the compounds of the present invention arecompounds represented by formula (III) as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, prodrugs and solvates thereof:

wherein X₁-X₅ are independently N or CR₂₁, where R₂₁ is independentlyselected from the group consisting of hydrogen, halogen, amino,substituted amino, hydroxy, substituted hydroxy, thiol, substitutedthiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkylamino, substituted or unsubstituted dialkylamino,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkylsulfonyl, CF₃, NO₂, CN, N₃, substituted carbonyl, sulfonyl, acyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, cycloalkyl, or substitutedcycloalkyl; M₁ is absent, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,aryl or heteroaryl; M₂ is absent, O, S, SO, SO₂, N(R₈), or C═O; M₃ isabsent, C═O, O, S, SO, SO₂ or N(R₈); M₄ is hydrogen, halogen, CN, N₃,hydroxy, substituted hydroxy, amino, substituted amino, CF₃, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocyclic, aryl orheteroaryl; and X, Y and Z are as previously defined. In one example, Xis S; Y is hydrogen; Z is amino; M₁-M₄ and X₁-X₅ are as defined above.

In one example, X₁-X₅ are independently N or CR₂₁, where R₂₁ isindependently selected from the group consisting of hydrogen, halogen,amino, hydroxy, thiol, alkyl, substituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylamino,substituted or unsubstituted dialkylamino, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkylsulfonyl, CF₃, NO₂, CN, N₃,sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, orsubstituted cycloalkyl; M₁ is absent, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, aryl or heteroaryl; M₂ is absent, O, S, SO, SO₂, N(R₈), or C═O;M₃ is absent, C═O, O, S, SO, SO₂ or N(R₈); M₄ is hydrogen, halogen, CN,N₃, hydroxy, amino, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,cycloalkyl, heterocyclic, aryl or heteroaryl; and X, Y and Z are aspreviously defined. In one example, X is S; Y is hydrogen; Z is amino;M₁-M₄ and X₁-X₅ are as defined above.

In a fourth embodiment of the compounds of the present invention arecompounds represented by formula (IV) as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, prodrugs and solvates thereof:

wherein X₂ and X₅ are independently CH or N; R₂₁ is independentlyselected from the group consisting of hydrogen, halogen, amino,substituted amino, hydroxy, substituted hydroxy, thiol, substitutedthiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkylamino, substituted or unsubstituted dialkylamino,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkylsulfonyl, CF₃, NO₂, CN, N₃, substituted carbonyl, sulfonyl, acyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, cycloalkyl, or substitutedcycloalkyl; Cy is a saturated or unsaturated fused 5-8 membered cyclicring optionally substituted with 0-3 heteroatom; M₁ is absent, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl or heteroaryl; M₂ is absent,O, S, SO, SO₂, N(R₈), or C═O; M₃ is absent, C═O, O, S, SO, SO₂ or N(R₈);M₄ is hydrogen, halogen, CN, N₃, hydroxy, substituted hydroxy, amino,substituted amino, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,cycloalkyl, heterocyclic, aryl or heteroaryl; and X, Y and Z are aspreviously defined. In one example, X is S; Y is hydrogen; Z is amino;R₂₁, M₁-M₄ and X₂, X₅ are as defined above.

In one example, X₂ and X₅ are independently CH or N; R₂₁ isindependently selected from the group consisting of hydrogen, halogen,amino, hydroxy, thiol, alkyl, substituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylamino,substituted or unsubstituted dialkylamino, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkylsulfonyl, CF₃, NO₂, CN, N₃,sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, orsubstituted cycloalkyl; Cy is a saturated or unsaturated fused 5-8membered cyclic ring optionally substituted with 0-3 heteroatom; M₁ isabsent, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl or heteroaryl;M₂ is absent, O, S, SO, SO₂, N(R₈), or C═O; M₃ is absent, C═O, O, S, SO,SO₂ or N(R₈); M₄ is hydrogen, halogen, CN, N₃, hydroxy, amino, CF₃,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocyclic,aryl or heteroaryl; and X, Y and Z are as previously defined. In oneexample, X is S; Y is hydrogen; Z is amino; R₂₁, M₁-M₄ and X₂, X₅ are asdefined above.

In a fifth embodiment of the compounds of the present invention arecompounds represented by formula (V) as illustrated below, or itsgeometric isomers, enantiomers, diastereomers, racemates,pharmaceutically acceptable salts, prodrugs and solvates thereof:

wherein X₂ and X₅ are independently CH or N; R₂₁ is independentlyselected from the group consisting of hydrogen, halogen, amino,substituted amino, hydroxy, substituted hydroxy, thiol, substitutedthiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkylamino, substituted or unsubstituted dialkylamino,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkylsulfonyl, CF₃, NO₂, CN, N₃, substituted carbonyl, sulfonyl, acyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, cycloalkyl, or substitutedcycloalkyl; Y₁ and Y₃ are independently O, S, N(R₈), CH(R₂₁); n is 1, 2,or 3; M₁ is absent, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl orheteroaryl; M₂ is absent, O, S, SO, SO₂, N(R₈), or C═O; M₃ is absent,C═O, O, S, SO, SO₂ or N(R₈); M₄ is hydrogen, halogen, CN, N₃, hydroxy,substituted hydroxy, amino, substituted amino, CF₃, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;R₁₀ and R₂₀ are independently hydrogen, alkyl, substituted alkyl, arylor substituted aryl; and X, Y and Z are as previously defined. In oneexample, X is S; Y is hydrogen; Z is amino; n, R₂₁, M₁-M₄, X₂, X₅, Y₁and Y₃ are as defined above.

In one example, X₂ and X₅ are independently CH or N; R₂₁ isindependently selected from the group consisting of hydrogen, halogen,amino, hydroxy, thiol, alkyl, substituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylamino,substituted or unsubstituted dialkylamino, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkylsulfonyl, CF₃, NO₂, CN, N₃,sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, orsubstituted cycloalkyl; Y₁ and Y₃ are independently O, S, N(R₈),CH(R₂₁); n is 1, 2, or 3; M₁ is absent, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, aryl or heteroaryl; M₂ is absent, O, S, SO, SO₂, N(R₈),or C═O; M₃ is absent, C═O, O, S, SO, SO₂ or N(R₈); M₄ is hydrogen,halogen, CN, N₃, hydroxy, amino, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; R₁₀ and R₂₀ areindependently hydrogen, alkyl, substituted alkyl, aryl or substitutedaryl; and X, Y and Z are as previously defined. In one example, X is S;Y is hydrogen; Z is amino; n, R₂₁, M₁-M₄, X₂, X₅, Y₁ and Y₃ are asdefined above.

Representative compounds according to the invention are those selectedfrom the Table A below or its geometric isomers, enantiomers,diastereomers, racemates, pharmaceutically acceptable salts, prodrugsand solvates thereof:

TABLE A Compound # Structure  1

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The invention further provides methods for the prevention or treatmentof diseases or conditions involving aberrant proliferation,differentiation or survival of cells. In one embodiment, the inventionfurther provides for the use of one or more compounds of the inventionin the manufacture of a medicament for halting or decreasing diseasesinvolving aberrant proliferation, differentiation, or survival of cells.In preferred embodiments, the disease is cancer or neurodegenerative. Inone embodiment, the invention relates to a method of treating cancer ina subject in need of treatment comprising administering to said subjecta therapeutically effective amount of a compound of the invention. Inone embodiment, the invention relates to a method of treating aneurodegenerative disease in a subject in need of treating comprisingadministering to said subject a therapeutically effective amount of thecompound of the invention.

The term “cancer” refers to any cancer caused by the proliferation ofmalignant neoplastic cells, such as tumors, neoplasms, carcinomas,sarcomas, leukemias, lymphomas and the like. For example, cancersinclude, but are not limited to, mesothelioma, leukemias and lymphomassuch as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheralT-cell lymphomas, lymphomas associated with human T-cell lymphotrophicvirus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-celllymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia,chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, andmultiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL),chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma,adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronicmyeloid leukemia (CML), or hepatocellular carcinoma. Further examplesinclude myelodisplastic syndrome, childhood solid tumors such as braintumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, andsoft-tissue sarcomas, common solid tumors of adults such as head andneck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal),genito urinary cancers (e.g., prostate, bladder, renal, uterine,ovarian, testicular), lung cancer (e.g., small-cell and non small cell),breast cancer, pancreatic cancer, melanoma and other skin cancers,stomach cancer, brain tumors, tumors related to Gorlin's syndrome (e.g.,medulloblastoma, meningioma, etc.), and liver cancer. Additionalexemplary forms of cancer which may be treated by the subject compoundsinclude, but are not limited to, cancer of skeletal or smooth muscle,stomach cancer, cancer of the small intestine, rectum carcinoma, cancerof the salivary gland, endometrial cancer, adrenal cancer, anal cancer,rectal cancer, parathyroid cancer, and pituitary cancer.

Additional cancers that the compounds described herein may be useful inpreventing, treating and studying are, for example, colon carcinoma,familiary adenomatous polyposis carcinoma and hereditary non-polyposiscolorectal cancer, or melanoma. Further, cancers include, but are notlimited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma,tongue carcinoma, salivary gland carcinoma, gastric carcinoma,adenocarcinoma, thyroid cancer (medullary and papillary thyroidcarcinoma), renal carcinoma, kidney parenchyma carcinoma, cervixcarcinoma, uterine corpus carcinoma, endometrium carcinoma, chorioncarcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumorssuch as glioblastoma, astrocytoma, meningioma, medulloblastoma andperipheral neuroectodermal tumors, gall bladder carcinoma, bronchialcarcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma,choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma,osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma,Ewing sarcoma, and plasmocytoma. In one aspect of the invention, thepresent invention provides for the use of one or more compounds of theinvention in the manufacture of a medicament for the treatment ofcancer.

In one embodiment, the present invention includes the use of one or morecompounds of the invention in the manufacture of a medicament thatprevents further aberrant proliferation, differentiation, or survival ofcells. For example, compounds of the invention may be useful inpreventing tumors from increasing in size or from reaching a metastaticstate. The subject compounds may be administered to halt the progressionor advancement of cancer. In addition, the instant invention includesuse of the subject compounds to prevent a recurrence of cancer.

This invention further embraces the treatment or prevention of cellproliferative disorders such as hyperplasias, dysplasias andpre-cancerous lesions. Dysplasia is the earliest form of pre-cancerouslesion recognizable in a biopsy by a pathologist. The subject compoundsmay be administered for the purpose of preventing said hyperplasias,dysplasias or pre-cancerous lesions from continuing to expand or frombecoming cancerous. Examples of pre-cancerous lesions may occur in skin,esophageal tissue, breast and cervical intra-epithelial tissue.

“Combination therapy” includes the administration of the subjectcompounds in further combination with other biologically activeingredients (such as, but not limited to, a second and differentantineoplastic agent) and non-drug therapies (such as, but not limitedto, surgery or radiation treatment). For instance, the compounds of theinvention can be used in combination with other pharmaceutically activecompounds, preferably compounds that are able to enhance the effect ofthe compounds of the invention. The compounds of the invention can beadministered simultaneously (as a single preparation or separatepreparation) or sequentially to the other drug therapy. In general, acombination therapy envisions administration of two or more drugs duringa single cycle or course of therapy.

In one aspect of the invention, the subject compounds may beadministered in combination with one or more separate agents thatmodulate protein kinases involved in various disease states. Examples ofsuch kinases may include, but are not limited to: serine/threoninespecific kinases, receptor tyrosine specific kinases and non-receptortyrosine specific kinases. Serine/threonine kinases include mitogenactivated protein kinases (MAPK), meiosis specific kinase (MEK), RAF andaurora kinase. Examples of receptor kinase families include epidermalgrowth factor receptor (EGFR) (e.g. HER₂/neu, HER₃, HER₄, ErbB, ErbB2,ErbB3, ErbB4, Xmrk, DER, Let23); fibroblast growth factor (FGF) receptor(e.g. FGF-R1, GFF-R₂/BEK/CEK3, FGF-R₃/CEK2, FGF-R₄/TKF, KGF-R);hepatocyte growth/scatter factor receptor (HGFR) (e.g. MET, RON, SEA,SEX); insulin receptor (e.g. IGFI-R); Eph (e.g. CEK5, CEK8, EBK, ECK,EEK, EHK-1, EHK-2, ELK, EPH, ERK, HEK, MDK2, MDK5, SEK); Axl (e.g.Mer/Nyk, Rse); RET; and platelet-derived growth factor receptor (PDGFR)(e.g. PDGFα-R, PDGβ-R, CSF1-R/FMS, SCF-R/C-KIT, VEGF-R/FLT, NEK/FLK1,FLT3/FLK2/STK-1). Non-receptor tyrosine kinase families include, but arenot limited to, BCR-ABL (e.g. p43^(ab1), ARG); BTK (e.g. ITK/EMT, TEC);CSK, FAK, FPS, JAK, SRC, BMX, FER, CDK and SYK.

In another aspect of the invention, the subject compounds may beadministered in combination with one or more separate agents thatmodulate non-kinase biological targets or processes. Such targetsinclude histone deacetylases (HDAC), DNA methyltransferase (DNMT), heatshock proteins (e.g. HSP90), and proteosomes.

In a preferred embodiment, subject compounds may be combined withantineoplastic agents (e.g. small molecules, monoclonal antibodies,antisense RNA, and fusion proteins) that inhibit one or more biologicaltargets such as Zolinza, Tarceva, Iressa, Tykerb, Gleevec, Sutent,Sprycel, Nexavar, Sorafinib, CNF2024, RG108, BMS387032, Affinitak,Avastin, Herceptin, Erbitux, AG24322, PD325901, ZD6474, PD184322,Obatodax, ABT737 and AEE788. Such combinations may enhance therapeuticefficacy over efficacy achieved by any of the agents alone and mayprevent or delay the appearance of resistant mutational variants.

In certain preferred embodiments, the compounds of the invention areadministered in combination with a chemotherapeutic agent.Chemotherapeutic agents encompass a wide range of therapeutic treatmentsin the field of oncology. These agents are administered at variousstages of the disease for the purposes of shrinking tumors, destroyingremaining cancer cells left over after surgery, inducing remission,maintaining remission and/or alleviating symptoms relating to the canceror its treatment. Examples of such agents include, but are not limitedto, alkylating agents such as mustard gas derivatives (Mechlorethamine,cylophosphamide, chlorambucil, melphalan, ifosfamide), ethylenimines(thiotepa, hexamethylmelanine), Alkylsulfonates (Busulfan), Hydrazinesand Triazines (Altretamine, Procarbazine, Dacarbazine and Temozolomide),Nitrosoureas (Carmustine, Lomustine and Streptozocin), Ifosfamide andmetal salts (Carboplatin, Cisplatin, and Oxaliplatin); plant alkaloidssuch as Podophyllotoxins (Etoposide and Tenisopide), Taxanes (Paclitaxeland Docetaxel), Vinca alkaloids (Vincristine, Vinblastine, Vindesine andVinorelbine), and Camptothecan analogs (Irinotecan and Topotecan);anti-tumor antibiotics such as Chromomycins (Dactinomycin andPlicamycin), Anthracyclines (Doxorubicin, Daunorubicin, Epirubicin,Mitoxantrone, Valrubicin and Idarubicin), and miscellaneous antibioticssuch as Mitomycin, Actinomycin and Bleomycin; anti-metabolites such asfolic acid antagonists (Methotrexate, Pemetrexed, Raltitrexed,Aminopterin), pyrimidine antagonists (5-Fluorouracil, Floxuridine,Cytarabine, Capecitabine, and Gemcitabine), purine antagonists(6-Mercaptopurine and 6-Thioguanine) and adenosine deaminase inhibitors(Cladribine, Fludarabine, Mercaptopurine, Clofarabine, Thioguanine,Nelarabine and Pentostatin); topoisomerase inhibitors such astopoisomerase I inhibitors (Ironotecan, topotecan) and topoisomerase IIinhibitors (Amsacrine, etoposide, etoposide phosphate, teniposide);monoclonal antibodies (Alemtuzumab, Gemtuzumab ozogamicin, Rituximab,Trastuzumab, Ibritumomab Tioxetan, Cetuximab, Panitumumab, Tositumomab,Bevacizumab); and miscellaneous anti-neoplastics such as ribonucleotidereductase inhibitors (Hydroxyurea); adrenocortical steroid inhibitor(Mitotane); enzymes (Asparaginase and Pegaspargase); anti-microtubuleagents (Estramustine); and retinoids (Bexarotene, Isotretinoin,Tretinoin (ATRA).

In certain preferred embodiments, the compounds of the invention areadministered in combination with a chemoprotective agent.Chemoprotective agents act to protect the body or minimize the sideeffects of chemotherapy. Examples of such agents include, but are notlimited to, amfostine, mesna, and dexrazoxane.

In one aspect of the invention, the subject compounds are administeredin combination with radiation therapy. Radiation is commonly deliveredinternally (implantation of radioactive material near cancer site) orexternally from a machine that employs photon (x-ray or gamma-ray) orparticle radiation. Where the combination therapy further comprisesradiation treatment, the radiation treatment may be conducted at anysuitable time so long as a beneficial effect from the co-action of thecombination of the therapeutic agents and radiation treatment isachieved. For example, in appropriate cases, the beneficial effect isstill achieved when the radiation treatment is temporally removed fromthe administration of the therapeutic agents, perhaps by days or evenweeks.

It will be appreciated that compound of the inventions can be useful intreating disorders such as, but not limited to: Anti-proliferativedisorders (e.g. cancers);

Neurodegenerative diseases including Huntington's disease, Polyglutaminedisease, Parkinson's disease, Alzheimer's disease, Seizures,Striatonigral degeneration, Progressive supranuclear palsy, Torsiondystonia, Spasmodic torticollis and dyskinesis, Familial tremor, Gillesde la Tourette syndrome, Diffuse Lewy body disease, Progressivesupranuclear palsy, Pick's disease, intracerebral hemorrhage, Primarylateral sclerosis, Spinal muscular atrophy, Amyotrophic lateralsclerosis, Hypertrophic interstitial polyneuropathy, Retinitispigmentosa, Hereditary optic atrophy, Hereditary spastic paraplegia,Progressive ataxia and Shy-Drager syndrome; Metabolic diseases includingType 2 diabetes; Degenerative diseases of the Eye including Glaucoma,Age-related macular degeneration, Rubeotic glaucoma; Inflammatorydiseases and/or Immune system disorders including Rheumatoid Arthritis(RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Hostdisease, Psoriasis, Asthma, Spondyloarthropathy, psoriasis, Crohn'sDisease, inflammatory bowel disease Colitis Ulcerosa, Alcoholichepatitis, Diabetes, Sjoegrens's syndrome, Multiple Sclerosis,Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain,Systemic Lupus Erythematosus; Disease involving angiogenesis includingcancer, psoriasis, rheumatoid arthritis; Psychological disordersincluding bipolar disease, schizophrenia, mania, depression anddementia; Cardiovascular Diseases including the prevention and treatmentof ischemia-related or reperfusion-related vascular and myocardialtissue damage, heart failure, restenosis and arteriosclerosis; Fibroticdiseases including liver fibrosis, cystic fibrosis and angiofibroma;Infectious diseases including Fungal infections, such as candidiasis orCandida Albicans, Bacterial infections, Viral infections, such as HerpesSimplex, poliovirus, rhinovirus and coxsackievirus, Protozoalinfections, such as Malaria, Leishmania infection, Trypanosoma bruceiinfection, Toxoplasmosis and coccidlosis and Haematopoietic disordersincluding thalassemia, anemia and sickle cell anemia.

In one embodiment, compounds of the invention can be used to induce orinhibit apoptosis, a physiological cell death process critical fornormal development and homeostasis. Alterations of apoptotic pathwayscontribute to the pathogenesis of a variety of human diseases. Compoundsof the invention, as modulators of apoptosis, will be useful in thetreatment of a variety of human diseases with abberations in apoptosisincluding cancer (particularly, but not limited to, follicularlymphomas, carcinomas with p53 mutations, hormone dependent tumors ofthe breast, prostate and ovary, and precancerous lesions such asfamilial adenomatous polyposis), viral infections (including, but notlimited to, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus andadenovirus), autoimmune diseases (including, but not limited to,systemic lupus, erythematosus, immune mediated glomerulonephritis,rheumatoid arthritis, psoriasis, inflammatory bowel diseases, andautoimmune diabetes mellitus), neurodegenerative disorders (including,but not limited to, Alzheimer's disease, AIDS-related dementia,Parkinson's disease, amyotrophic lateral sclerosis, retinitispigmentosa, spinal muscular atrophy and cerebellar degeneration), AIDS,myelodysplastic syndromes, aplastic anemia, ischemic injury associatedmyocardial infarctions, stroke and reperfusion injury, arrhythmia,atherosclerosis, toxin-induced or alcohol induced liver diseases,hematological diseases (including, but not limited to, chronic anemiaand aplastic anemia), degenerative diseases of the musculoskeletalsystem (including, but not limited to, osteoporosis and arthritis),aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis,kidney diseases, and cancer pain.

In addition to anti-cancer and antitumorigenic activity, HSP90inhibitors have also been implicated in a wide variety of otherutilities, including use as anti-inflammation agents, anti-infectiousdisease agents, agents for treating autoimmunity, agents for treatingstroke, ischemia, multiple sclerosis, cardiac disorders, central nervoussystem related disorders and agents useful in promoting nerveregeneration (see, e.g., Rosen et al. WO 02/09696 (PCT/US01/23640);Degranco et al. WO 99/51223 (PCT/US99/07242); Gold, U.S. Pat. No.6,210,974 B1; DeFranco et al., U.S. Pat. No. 6,174,875). There arereports in the literature that fibrogenetic disorders including but notlimited to scleroderma, polymyositis, systemic lupus, rheumatoidarthritis, liver cirrhosis, keloid formation, interstitial nephritis,and pulmonary fibrosis also may be treatable with HSP90 inhibitors.

In one aspect, the invention provides the use of compounds of theinvention for the treatment and/or prevention of immune response orimmune-mediated responses and diseases, such as the prevention ortreatment of rejection following transplantation of synthetic or organicgrafting materials, cells, organs or tissue to replace all or part ofthe function of tissues, such as heart, kidney, liver, bone marrow,skin, cornea, vessels, lung, pancreas, intestine, limb, muscle, nervetissue, duodenum, small-bowel, pancreatic-islet-cell, includingxeno-transplants, etc.; to treat or prevent graft-versus-host disease,autoimmune diseases, such as rheumatoid arthritis, systemic lupuserythematosus, thyroiditis, Hashimoto's thyroiditis, multiple sclerosis,myasthenia gravis, type I diabetes uveitis, juvenile-onset orrecent-onset diabetes mellitus, uveitis, Graves disease, psoriasis,atopic dermatitis, Crohn's disease, ulcerative colitis, vasculitis,auto-antibody mediated diseases, aplastic anemia, Evan's syndrome,autoimmune hemolytic anemia, and the like; and further to treatinfectious diseases causing aberrant immune response and/or activation,such as traumatic or pathogen induced immune disregulation, includingfor example, that which are caused by hepatitis B and C infections, HIV,staphylococcus aureus infection, viral encephalitis, sepsis, parasiticdiseases wherein damage is induced by an inflammatory response (e.g.,leprosy); and to prevent or treat circulatory diseases, such asarteriosclerosis, atherosclerosis, vasculitis, polyarteritis nodosa andmyocarditis. In addition, the present invention may be used toprevent/suppress an immune response associated with a gene therapytreatment, such as the introduction of foreign genes into autologouscells and expression of the encoded product. Thus in one embodiment, theinvention relates to a method of treating an immune response disease ordisorder or an immune-mediated response or disorder in a subject in needof treatment comprising administering to said subject a therapeuticallyeffective amount of a compound of the invention.

In one aspect, the invention provides the use of compounds of theinvention in the treatment of a variety of neurodegenerative diseases, anon-exhaustive list of which is: I. Disorders characterized byprogressive dementia in the absence of other prominent neurologic signs,such as Alzheimer's disease; Senile dementia of the Alzheimer type; andPick's disease (lobar atrophy); II. Syndromes combining progressivedementia with other prominent neurologic abnormalities such as: A)syndromes appearing mainly in adults (e.g., Huntington's disease,Multiple system atrophy combining dementia with ataxia and/ormanifestations of Parkinson's disease, Progressive supranuclear palsy(Steel-Richardson-Olszewski), diffuse Lewy body disease, andcorticodentatonigral degeneration); and B) syndromes appearing mainly inchildren or young adults (e.g., Hallervorden-Spatz disease andprogressive familial myoclonic epilepsy); III. Syndromes of graduallydeveloping abnormalities of posture and movement such as paralysisagitans (Parkinson's disease), striatonigral degeneration, progressivesupranuclear palsy, torsion dystonia (torsion spasm; dystonia musculorumdeformans), spasmodic torticollis and other dyskinesis, familial tremor,and Gilles de la Tourette syndrome; IV. Syndromes of progressive ataxiasuch as cerebellar degenerations (e.g., cerebellar cortical degenerationand olivopontocerebellar atrophy (OPCA)); and spinocerebellardegeneration (Friedreich's atazia and related disorders); V. Syndrome ofcentral autonomic nervous system failure (Shy-Drager syndrome); VI.Syndromes of muscular weakness and wasting without sensory changes(motoneuron disease such as amyotrophic lateral sclerosis, spinalmuscular atrophy (e.g., infantile spinal muscular atrophy(Werdnig-Hoffman), juvenile spinal muscular atrophy(Wohlfart-Kugelberg-Welander) and other forms of familial spinalmuscular atrophy), primary lateral sclerosis, and hereditary spasticparaplegia; VII. Syndromes combining muscular weakness and wasting withsensory changes (progressive neural muscular atrophy; chronic familialpolyneuropathies) such as peroneal muscular atrophy(Charcot-Marie-Tooth), hypertrophic interstitial polyneuropathy(Dejerine-Sottas), and miscellaneous forms of chronic progressiveneuropathy; and VIII. Syndromes of progressive visual loss such aspigmentary degeneration of the retina (retinitis pigmentosa), andhereditary optic atrophy (Leber's disease). Furthermore, compounds ofthe invention can be implicated in chromatin remodeling.

The invention encompasses pharmaceutical compositions comprisingpharmaceutically acceptable salts of the compounds of the invention asdescribed above. The invention also encompasses pharmaceuticalcompositions comprising hydrates of the compounds of the invention. Theterm “hydrate” includes but is not limited to hemihydrate, monohydrate,dihydrate, trihydrate and the like. The invention further encompassespharmaceutical compositions comprising any solid or liquid physical formof the compound of the invention. For example, the compounds can be in acrystalline form, in amorphous form, and have any particle size. Theparticles may be micronized, or may be agglomerated, particulategranules, powders, oils, oily suspensions or any other form of solid orliquid physical form.

The compounds of the invention, and derivatives, fragments, analogs,homologs, pharmaceutically acceptable salts or hydrate thereof can beincorporated into pharmaceutical compositions suitable foradministration, together with a pharmaceutically acceptable carrier orexcipient. Such compositions typically comprise a therapeuticallyeffective amount of any of the compounds above, and a pharmaceuticallyacceptable carrier. Preferably, the effective amount when treatingcancer is an amount effective to selectively induce terminaldifferentiation of suitable neoplastic cells and less than an amountwhich causes toxicity in a patient.

It will be appreciated that compounds of the invention can be used incombination with an immunotherapeutic agent. One form of immunotherapyis the generation of an active systemic tumor-specific immune responseof host origin by administering a vaccine composition at a site distantfrom the tumor. Various types of vaccines have been proposed, includingisolated tumor-antigen vaccines and anti-idiotype vaccines. Anotherapproach is to use tumor cells from the subject to be treated, or aderivative of such cells (reviewed by Schirrmacher et al. (1995) J.Cancer Res. Clin. Oncol. 121:487). In U.S. Pat. No. 5,484,596, Hanna Jr.et al. claim a method for treating a resectable carcinoma to preventrecurrence or metastases, comprising surgically removing the tumor,dispersing the cells with collagenase, irradiating the cells, andvaccinating the patient with at least three consecutive doses of about10⁷ cells.

It will be appreciated that the compounds of the invention mayadvantageously be used in conjunction with one or more other therapeuticagents. Examples of suitable agents for adjunctive therapy include a5HT₁ agonist, such as a triptan (e.g. sumatriptan or naratriptan); anadenosine A1 agonist; an EP ligand; an NMDA modulator, such as a glycineantagonist; a sodium channel blocker (e.g. lamotrigine); a substance Pantagonist (e.g. an NK₁ antagonist); a cannabinoid; acetaminophen orphenacetin; a 5-lipoxygenase inhibitor; a leukotriene receptorantagonist; a DMARD (e.g. methotrexate); gabapentin and relatedcompounds; a tricyclic antidepressant (e.g. amitryptilline); a neuronestabilising antiepileptic drug; a mono-aminergic uptake inhibitor (e.g.venlafaxine); a matrix metalloproteinase inhibitor; a nitric oxidesynthase (NOS) inhibitor, such as an iNOS or an nNOS inhibitor; aninhibitor of the release, or action, of tumour necrosis factor .alpha.;an antibody therapy, such as a monoclonal antibody therapy; an antiviralagent, such as a nucleoside inhibitor (e.g. lamivudine) or an immunesystem modulator (e.g. interferon); an opioid analgesic; a localanaesthetic; a stimulant, including caffeine; an H₂-antagonist (e.g.ranitidine); a proton pump inhibitor (e.g. omeprazole); an antacid (e.g.aluminum or magnesium hydroxide; an antiflatulent (e.g. simethicone); adecongestant (e.g. phenylephrine, phenylpropanolamine, pseudoephedrine,oxymetazoline, epinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxyephedrine); an antitussive (e.g. codeine,hydrocodone, carmiphen, carbetapentane, or dextramethorphan); adiuretic; or a sedating or non-sedating antihistamine.

Compounds of the invention may be administered by any suitable means,including, without limitation, parenteral, intravenous, intramuscular,subcutaneous, implantation, oral, sublingual, buccal, nasal, pulmonary,transdermal, topical, vaginal, rectal, and transmucosal administrationsor the like. Topical administration can also involve the use oftransdermal administration such as transdermal patches or iontophoresisdevices. Pharmaceutical preparations include a solid, semisolid orliquid preparation (tablet, pellet, troche, capsule, suppository, cream,ointment, aerosol, powder, liquid, emulsion, suspension, syrup,injection etc.) containing a compound of the invention as an activeingredient, which is suitable for selected mode of administration. Inone embodiment, the pharmaceutical compositions are administered orally,and are thus formulated in a form suitable for oral administration,i.e., as a solid or a liquid preparation. Suitable solid oralformulations include tablets, capsules, pills, granules, pellets,sachets and effervescent, powders, and the like. Suitable liquid oralformulations include solutions, suspensions, dispersions, emulsions,oils and the like. In one embodiment of the present invention, thecomposition is formulated in a capsule. In accordance with thisembodiment, the compositions of the present invention comprise inaddition to the active compound and the inert carrier or diluent, a hardgelatin capsule.

Any inert excipient that is commonly used as a carrier or diluent may beused in the formulations of the present invention, such as for example,a gum, a starch, a sugar, a cellulosic material, an acrylate, ormixtures thereof. A preferred diluent is microcrystalline cellulose. Thecompositions may further comprise a disintegrating agent (e.g.,croscarmellose sodium) and a lubricant (e.g., magnesium stearate), andin addition may comprise one or more additives selected from a binder, abuffer, a protease inhibitor, a surfactant, a solubilizing agent, aplasticizer, an emulsifier, a stabilizing agent, a viscosity increasingagent, a sweetener, a film forming agent, or any combination thereof.Furthermore, the compositions of the present invention may be in theform of controlled release or immediate release formulations.

For liquid formulations, pharmaceutically acceptable carriers may beaqueous or non-aqueous solutions, suspensions, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, alcoholic/aqueous solutions, emulsions orsuspensions, including saline and buffered media. Examples of oils arethose of petroleum, animal, vegetable, or synthetic origin, for example,peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, andfish-liver oil. Solutions or suspensions can also include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid(EDTA); buffers such as acetates, citrates or phosphates, and agents forthe adjustment of tonicity such as sodium chloride or dextrose. The pHcan be adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide.

In addition, the compositions may further comprise binders (e.g.,acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone),disintegrating agents (e.g., cornstarch, potato starch, alginic acid,silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodiumstarch glycolate, Primogel), buffers (e.g., tris-HCl., acetate,phosphate) of various pH and ionic strength, additives such as albuminor gelatin to prevent absorption to surfaces, detergents (e.g., Tween20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors,surfactants (e.g., sodium lauryl sulfate), permeation enhancers,solubilizing agents (e.g., glycerol, polyethylene glycerol), a glidant(e.g., colloidal silicon dioxide), anti-oxidants (e.g., ascorbic acid,sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g.,hydroxypropyl cellulose, hydroxypropylmethyl cellulose), viscosityincreasing agents (e.g., carbomer, colloidal silicon dioxide, ethylcellulose, guar gum), sweeteners (e.g., sucrose, aspartame, citricacid), flavoring agents (e.g., peppermint, methyl salicylate, or orangeflavoring), preservatives (e.g., Thimerosal, benzyl alcohol, parabens),lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol,sodium lauryl sulfate), flow-aids (e.g., colloidal silicon dioxide),plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers(e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate),polymer coatings (e.g., poloxamers or poloxamines), coating and filmforming agents (e.g., ethyl cellulose, acrylates, polymethacrylates)and/or adjuvants.

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

It is especially advantageous to formulate oral compositions in dosageunit form for ease of administration and uniformity of dosage. Dosageunit form as used herein refers to physically discrete units suited asunitary dosages for the subject to be treated; each unit containing apredetermined quantity of active compound calculated to produce thedesired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms ofthe invention are dictated by and directly dependent on the uniquecharacteristics of the active compound and the particular therapeuticeffect to be achieved, and the limitations inherent in the art ofcompounding such an active compound for the treatment of individuals.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

Daily administration may be repeated continuously for a period ofseveral days to several years. Oral treatment may continue for betweenone week and the life of the patient. Preferably the administration maytake place for five consecutive days after which time the patient can beevaluated to determine if further administration is required. Theadministration can be continuous or intermittent, e.g., treatment for anumber of consecutive days followed by a rest period. The compounds ofthe present invention may be administered intravenously on the first dayof treatment, with oral administration on the second day and allconsecutive days thereafter.

The preparation of pharmaceutical compositions that contain an activecomponent is well understood in the art, for example, by mixing,granulating, or tablet-forming processes. The active therapeuticingredient is often mixed with excipients that are pharmaceuticallyacceptable and compatible with the active ingredient. For oraladministration, the active agents are mixed with additives customary forthis purpose, such as vehicles, stabilizers, or inert diluents, andconverted by customary methods into suitable forms for administration,such as tablets, coated tablets, hard or soft gelatin capsules, aqueous,alcoholic or oily solutions and the like as detailed above.

The amount of the compound administered to the patient is less than anamount that would cause toxicity in the patient. In certain embodiments,the amount of the compound that is administered to the patient is lessthan the amount that causes a concentration of the compound in thepatient's plasma to equal or exceed the toxic level of the compound.Preferably, the concentration of the compound in the patient's plasma ismaintained at about 10 nM. In one embodiment, the concentration of thecompound in the patient's plasma is maintained at about 25 nM. In oneembodiment, the concentration of the compound in the patient's plasma ismaintained at about 50 nM. In one embodiment, the concentration of thecompound in the patient's plasma is maintained at about 100 nM. In oneembodiment, the concentration of the compound in the patient's plasma ismaintained at about 500 nM. In one embodiment, the concentration of thecompound in the patient's plasma is maintained at about 1000 nM. In oneembodiment, the concentration of the compound in the patient's plasma ismaintained at about 2500 nM. In one embodiment, the concentration of thecompound in the patient's plasma is maintained at about 5000 nM. Theoptimal amount of the compound that should be administered to thepatient in the practice of the present invention will depend on theparticular compound used and the type of cancer being treated.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

An “aliphatic group” or “aliphatic” is non-aromatic moiety that may besaturated (e.g. single bond) or contain one or more units ofunsaturation, e.g., double and/or triple bonds. An aliphatic group maybe straight chained, branched or cyclic, contain carbon, hydrogen or,optionally, one or more heteroatoms and may be substituted orunsubstituted. An aliphatic group, when used as a linker, preferablycontains between about 1 and about 24 atoms, more preferably betweenabout 4 to about 24 atoms, more preferably between about 4-12 atoms,more typically between about 4 and about 8 atoms. An aliphatic group,when used as a substituent, preferably contains between about 1 andabout 24 atoms, more preferably between about 1 to about 10 atoms, morepreferably between about 1-8 atoms, more typically between about 1 andabout 6 atoms. In addition to aliphatic hydrocarbon groups, aliphaticgroups include, for example, polyalkoxyalkyls, such as polyalkyleneglycols, polyamines, and polyimines, for example. Such aliphatic groupsmay be further substituted. It is understood that aliphatic groupsinclude alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl groups described herein.

The term “substituted carbonyl” includes compounds and moieties whichcontain a carbon connected with a double bond to an oxygen atom, andtautomeric forms thereof. Examples of moieties that contain asubstituted carbonyl include aldehydes, ketones, carboxylic acids,amides, esters, anhydrides, etc. The term “carbonyl moiety” refers togroups such as “alkylcarbonyl” groups wherein an alkyl group iscovalently bound to a carbonyl group, “alkenylcarbonyl” groups whereinan alkenyl group is covalently bound to a carbonyl group,“alkynylcarbonyl” groups wherein an alkynyl group is covalently bound toa carbonyl group, “arylcarbonyl” groups wherein an aryl group iscovalently attached to the carbonyl group. Furthermore, the term alsorefers to groups wherein one or more heteroatoms are covalently bondedto the carbonyl moiety. For example, the term includes moieties such as,for example, aminocarbonyl moieties (wherein a nitrogen atom is bound tothe carbon of the carbonyl group, e.g., an amide).

The term “acyl” refers to hydrogen, alkyl, partially saturated or fullysaturated cycloalkyl, partially saturated or fully saturatedheterocycle, aryl, and heteroaryl substituted carbonyl groups. Forexample, acyl includes groups such as (C₁-C₆)alkanoyl (e.g., formyl,acetyl, propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.),(C₃-C₆)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl,pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl,tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl(e.g., thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl,furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl,benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl,cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl groupmay be any one of the groups described in the respective definitions.When indicated as being “optionally substituted”, the acyl group may beunsubstituted or optionally substituted with one or more substituents(typically, one to three substituents) independently selected from thegroup of substituents listed below in the definition for “substituted”or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion ofthe acyl group may be substituted as described above in the preferredand more preferred list of substituents, respectively. The term “alkyl”embraces linear or branched radicals having one to about twenty carbonatoms or, preferably, one to about twelve carbon atoms. More preferredalkyl radicals are “lower alkyl” radicals having one to about ten carbonatoms. Most preferred are lower alkyl radicals having one to about eightcarbon atoms. Examples of such radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl and the like.

The term “alkenyl” embraces linear or branched radicals having at leastone carbon-carbon double bond of two to about twenty carbon atoms or,preferably, two to about twelve carbon atoms. More preferred alkenylradicals are “lower alkenyl” radicals having two to about ten carbonatoms and more preferably about two to about eight carbon atoms.Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyland 4-methylbutenyl. The terms “alkenyl”, and “lower alkenyl”, embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations.

The term “alkynyl” embraces linear or branched radicals having at leastone carbon-carbon triple bond of two to about twenty carbon atoms or,preferably, two to about twelve carbon atoms. More preferred alkynylradicals are “lower alkynyl” radicals having two to about ten carbonatoms and more preferably about two to about eight carbon atoms.Examples of alkynyl radicals include propargyl, 1-propynyl, 2-propynyl,1-butyne, 2-butynyl and 1-pentynyl.

The term “cycloalkyl” embraces saturated carbocyclic radicals havingthree to about twelve carbon atoms. The term “cycloalkyl” embracessaturated carbocyclic radicals having three to about twelve carbonatoms. More preferred cycloalkyl radicals are “lower cycloalkyl”radicals having three to about eight carbon atoms. Examples of suchradicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “cycloalkenyl” embraces partially unsaturated carbocyclicradicals having three to twelve carbon atoms. Cycloalkenyl radicals thatare partially unsaturated carbocyclic radicals that contain two doublebonds (that may or may not be conjugated) can be called“cycloalkyldienyl”. More preferred cycloalkenyl radicals are “lowercycloalkenyl” radicals having four to about eight carbon atoms. Examplesof such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term “alkoxy” embraces linear or branched oxy-containing radicalseach having alkyl portions of one to about one to about twenty carbonatoms or, preferably, one to about twelve carbon atoms. More preferredalkoxy radicals are “lower alkoxy” radicals having one to about tencarbon atoms and more preferably having one to about eight carbon atoms.Examples of such radicals include methoxy, ethoxy, propoxy, butoxy andtert-butoxy.

The term “alkoxyalkyl” embraces alkyl radicals having one or more alkoxyradicals attached to the alkyl radical, that is, to form monoalkoxyalkyland dialkoxyalkyl radicals.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl.

The terms “heterocyclyl”, “heterocycle” “heterocyclic” or “heterocyclo”embrace saturated, partially unsaturated and unsaturatedheteroatom-containing ring-shaped radicals, which can also be called“heterocyclyl”, “heterocycloalkenyl” and “heteroaryl” correspondingly,where the heteroatoms may be selected from nitrogen, sulfur and oxygen.Examples of saturated heterocyclyl radicals include saturated 3 to6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partiallyunsaturated heterocyclyl radicals include dihydrothiophene,dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicalsmay include a pentavalent nitrogen, such as in tetrazolium andpyridinium radicals. The term “heterocycle” also embraces radicals whereheterocyclyl radicals are fused with aryl or cycloalkyl radicals.Examples of such fused bicyclic radicals include benzofuran,benzothiophene, and the like.

The term “heteroaryl” embraces unsaturated heterocyclyl radicals.Examples of heteroaryl radicals include unsaturated 3 to 6 memberedheteromonocyclic group containing 1 to 4 nitrogen atoms, for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensedheterocyclyl group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term “heterocycloalkyl” embraces heterocyclo-substituted alkylradicals. More preferred heterocycloalkyl radicals are “lowerheterocycloalkyl” radicals having one to six carbon atoms in theheterocycloalkyl radicals.

The term “alkylthio” embraces radicals containing a linear or branchedalkyl radical, of one to about ten carbon atoms attached to a divalentsulfur atom. Preferred alkylthio radicals have alkyl radicals of one toabout twenty carbon atoms or, preferably, one to about twelve carbonatoms. More preferred alkylthio radicals have alkyl radicals are “loweralkylthio” radicals having one to about ten carbon atoms. Most preferredare alkylthio radicals having lower alkyl radicals of one to about eightcarbon atoms. Examples of such lower alkylthio radicals are methylthio,ethylthio, propylthio, butylthio and hexylthio.

The terms “aralkyl” or “arylalkyl” embrace aryl-substituted alkylradicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl,and diphenylethyl.

The term “aryloxy” embraces aryl radicals attached through an oxygenatom to other radicals.

The terms “aralkoxy” or “arylalkoxy” embrace aralkyl radicals attachedthrough an oxygen atom to other radicals.

The term “aminoalkyl” embraces alkyl radicals substituted with aminoradicals. Preferred aminoalkyl radicals have alkyl radicals having aboutone to about twenty carbon atoms or, preferably, one to about twelvecarbon atoms. More preferred aminoalkyl radicals are “lower aminoalkyl”that have alkyl radicals having one to about ten carbon atoms. Mostpreferred are aminoalkyl radicals having lower alkyl radicals having oneto eight carbon atoms. Examples of such radicals include aminomethyl,aminoethyl, and the like.

The term “alkylamino” denotes amino groups which are substituted withone or two alkyl radicals. Preferred alkylamino radicals have alkylradicals having about one to about twenty carbon atoms or, preferably,one to about twelve carbon atoms. More preferred alkylamino radicals are“lower alkylamino” that have alkyl radicals having one to about tencarbon atoms. Most preferred are alkylamino radicals having lower alkylradicals having one to about eight carbon atoms. Suitable loweralkylamino may be monosubstituted N-alkylamino or disubstitutedN,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino or the like.

The term “substituted” refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent including, but not limited to: halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, thiol, alkylthio, oxo, thioxy, arylthio,alkylthioalkyl, arylthioalkyl, alkyl sulfonyl, alkylsulfonylalkyl,arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl,alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl,haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino,alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl,carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl,aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonicacid, aryl, heteroaryl, heterocyclic, and aliphatic. It is understoodthat the substituent may be further substituted.

For simplicity, chemical moieties are defined and referred to throughoutcan be univalent chemical moieties (e.g., alkyl, aryl, etc.) ormultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, an “alkyl” moiety can bereferred to a monovalent radical (e.g. CH₃—CH₂—), or in other instances,a bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂—), which is equivalent to the term “alkylene.” Similarly, incircumstances in which divalent moieties are required and are stated asbeing “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”,“heteroaryl”, “heterocyclic”, “alkyl” “alkenyl”, “alkynyl”, “aliphatic”,or “cycloalkyl”, those skilled in the art will understand that the termsalkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”, “heteroaryl”,“heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”, “aliphatic”, or“cycloalkyl” refer to the corresponding divalent moiety.

The terms “halogen” or “halo” as used herein, refers to an atom selectedfrom fluorine, chlorine, bromine and iodine.

As used herein, the term “aberrant proliferation” refers to abnormalcell growth.

The phrase “adjunctive therapy” encompasses treatment of a subject withagents that reduce or avoid side effects associated with the combinationtherapy of the present invention, including, but not limited to, thoseagents, for example, that reduce the toxic effect of anticancer drugs,e.g., bone resorption inhibitors, cardioprotective agents; prevent orreduce the incidence of nausea and vomiting associated withchemotherapy, radiotherapy or operation; or reduce the incidence ofinfection associated with the administration of myelosuppressiveanticancer drugs.

The term “angiogenesis,” as used herein, refers to the formation ofblood vessels. Specifically, angiogenesis is a multi-step process inwhich endothelial cells focally degrade and invade through their ownbasement membrane, migrate through interstitial stroma toward anangiogenic stimulus, proliferate proximal to the migrating tip, organizeinto blood vessels, and reattach to newly synthesized basement membrane(see Folkman et al., Adv. Cancer Res., Vol. 43, pp. 175-203 (1985)).Anti-angiogenic agents interfere with this process. Examples of agentsthat interfere with several of these steps include thrombospondin-1,angiostatin, endostatin, interferon alpha and compounds such as matrixmetalloproteinase (MMP) inhibitors that block the actions of enzymesthat clear and create paths for newly forming blood vessels to follow;compounds, such as .alpha.v.beta.3 inhibitors, that interfere withmolecules that blood vessel cells use to bridge between a parent bloodvessel and a tumor; agents, such as specific COX-2 inhibitors, thatprevent the growth of cells that form new blood vessels; andprotein-based compounds that simultaneously interfere with several ofthese targets.

The term “apoptosis” as used herein refers to programmed cell death assignaled by the nuclei in normally functioning human and animal cellswhen age or state of cell health and condition dictates. An “apoptosisinducing agent” triggers the process of programmed cell death.

The term “cancer” as used herein denotes a class of diseases ordisorders characterized by uncontrolled division of cells and theability of these cells to invade other tissues, either by direct growthinto adjacent tissue through invasion or by implantation into distantsites by metastasis.

The term “compound” is defined herein to include pharmaceuticallyacceptable salts, solvates, hydrates, polymorphs, enantiomers,diastereoisomers, racemates and the like of the compounds having aformula as set forth herein.

The term “devices” refers to any appliance, usually mechanical orelectrical, designed to perform a particular function.

As used herein, the term “dysplasia” refers to abnormal cell growth.

The term “hyperplasia,” as used herein, refers to excessive celldivision or growth.

The phrase an “immunotherapeutic agent” refers to agents used totransfer the immunity of an immune donor, e.g., another person or ananimal, to a host by inoculation. The term embraces the use of serum orgamma globulin containing performed antibodies produced by anotherindividual or an animal; nonspecific systemic stimulation; adjuvants;active specific immunotherapy; and adoptive immunotherapy. Adoptiveimmunotherapy refers to the treatment of a disease by therapy or agentsthat include host inoculation of sensitized lymphocytes, transferfactor, immune RNA, or antibodies in serum or gamma globulin.

The term “inhibition,” in the context of neoplasia, tumor growth ortumor cell growth, may be assessed by delayed appearance of primary orsecondary tumors, slowed development of primary or secondary tumors,decreased occurrence of primary or secondary tumors, slowed or decreasedseverity of secondary effects of disease, arrested tumor growth andregression of tumors, among others. In the extreme, complete inhibition,is referred to herein as prevention or chemoprevention.

The term “metastasis,” as used herein, refers to the migration of cancercells from the original tumor site through the blood and lymph vesselsto produce cancers in other tissues. Metastasis also is the term usedfor a secondary cancer growing at a distant site.

The term “neoplasm,” as used herein, refers to an abnormal mass oftissue that results from excessive cell division. Neoplasms may bebenign (not cancerous), or malignant (cancerous) and may also be calleda tumor. The term “neoplasia” is the pathological process that resultsin tumor formation.

As used herein, the term “pre-cancerous” refers to a condition that isnot malignant, but is likely to become malignant if left untreated.

The term “proliferation” refers to cells undergoing mitosis.

The phrase “HSP90 related disease or disorder” refers to a disease ordisorder characterized by inappropriate HSP90 activity or over-activityof the HSP90. Inappropriate activity refers to either; (i) HSP90expression in cells which normally do not express HSP90; (ii) increasedHSP90 expression leading to unwanted cell proliferation, differentiationand/or growth; or, (iii) decreased HSP90 expression leading to unwantedreductions in cell proliferation, differentiation and/or growth.Over-activity of HSP90 refers to either amplification of the geneencoding a particular HSP90 or production of a level of HSP90 activitywhich can correlate with a cell proliferation, differentiation and/orgrowth disorder (that is, as the level of the HSP90 increases, theseverity of one or more of the symptoms of the cellular disorderincreases).

The phrase a “radio therapeutic agent” refers to the use ofelectromagnetic or particulate radiation in the treatment of neoplasia.

The term “recurrence” as used herein refers to the return of cancerafter a period of remission. This may be due to incomplete removal ofcells from the initial cancer and may occur locally (the same site ofinitial cancer), regionally (in vicinity of initial cancer, possibly inthe lymph nodes or tissue), and/or distally as a result of metastasis.

The term “treatment” refers to any process, action, application,therapy, or the like, wherein a mammal, including a human being, issubject to medical aid with the object of improving the mammal'scondition, directly or indirectly.

The term “vaccine” includes agents that induce the patient's immunesystem to mount an immune response against the tumor by attacking cellsthat express tumor associated antigens (Teas).

As used herein, the term “effective amount of the subject compounds,”with respect to the subject method of treatment, refers to an amount ofthe subject compound which, when delivered as part of desired doseregimen, brings about, e.g. a change in the rate of cell proliferationand/or state of differentiation and/or rate of survival of a cell toclinically acceptable standards. This amount may further relieve to someextent one or more of the symptoms of a neoplasia disorder, including,but is not limited to: 1) reduction in the number of cancer cells; 2)reduction in tumor size; 3) inhibition (i.e., slowing to some extent,preferably stopping) of cancer cell infiltration into peripheral organs;4) inhibition (i.e., slowing to some extent, preferably stopping) oftumor metastasis; 5) inhibition, to some extent, of tumor growth; 6)relieving or reducing to some extent one or more of the symptomsassociated with the disorder; and/or 7) relieving or reducing the sideeffects associated with the administration of anticancer agents.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid or inorganic acid. Examples of pharmaceuticallyacceptable nontoxic acid addition salts include, but are not limited to,salts of an amino group formed with inorganic acids such as hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloricacid or with organic acids such as acetic acid, maleic acid, tartaricacid, citric acid, succinic acid lactobionic acid or malonic acid or byusing other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include, but are not limited to,adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. “Prodrug”, as used herein means a compound which isconvertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of the invention. Various forms of prodrugs are known in theart, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design andApplication of Prodrugs, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug DeliverReviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); and Bernard Testa &Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

As used herein, “pharmaceutically acceptable carrier” is intended toinclude any and all solvents, dispersion media, coatings, antibacterialand antifungal agents, isotonic and absorption delaying agents, and thelike, compatible with pharmaceutical administration, such as sterilepyrogen-free water. Suitable carriers are described in the most recentedition of Remington's Pharmaceutical Sciences, a standard referencetext in the field, which is incorporated herein by reference. Preferredexamples of such carriers or diluents include, but are not limited to,water, saline, finger's solutions, dextrose solution, and 5% human serumalbumin. Liposomes and non-aqueous vehicles such as fixed oils may alsobe used. The use of such media and agents for pharmaceutically activesubstances is well known in the art. Except insofar as any conventionalmedia or agent is incompatible with the active compound, use thereof inthe compositions is contemplated. Supplementary active compounds canalso be incorporated into the compositions.

As used herein, the term “pre-cancerous” refers to a condition that isnot malignant, but is likely to become malignant if left untreated.

The term “subject” as used herein refers to an animal. Preferably theanimal is a mammal. More preferably the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P.G.M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers and/or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. The configuration ofany carbon-carbon double bond appearing herein is selected forconvenience only and is not intended to designate a particularconfiguration unless the text so states; thus a carbon-carbon doublebond or carbon-heteroatom double bond depicted arbitrarily herein astrans may be cis, trans, or a mixture of the two in any proportion.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;cyclodextrins such as alpha-(α), beta- (β) and gamma- (γ) cyclodextrins;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of whichare incorporated herein by reference). A discussion of pulmonarydelivery of antibiotics is also found in U.S. Pat. No. 6,014,969,incorporated herein by reference.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of the compounddescribed above may range from about 0.1 mg/Kg to about 500 mg/Kg,preferably from about 1 to about 50 mg/Kg. Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents. It will be understood, however, that thetotal daily usage of the compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the formulae described herein can, for example, beadministered by injection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.1 toabout 500 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with pharmaceutically excipients or carriers toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Alternatively,such preparations may contain from about 20% to about 80% activecompound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

Synthetic Methods

The compounds of the invention, or a pharmaceutically-acceptable saltthereof, may be prepared by any process known to be applicable to thepreparation of chemically-related compounds. Suitable processes formaking certain intermediates include, for example, those illustrated inPCT publication numbers WO02/36075, WO03/037860 and WO2006084030.Necessary starting materials may be obtained by standard procedures oforganic chemistry. The preparation of such starting materials isdescribed within the accompanying non-limiting Examples. Alternativelynecessary starting materials are obtainable by analogous procedures tothose illustrated which are within the ordinary skill of a chemist.

The compounds and processes of the present invention will be betterunderstood in connection with the following representative syntheticschemes that illustrate the methods by which the compounds of theinvention may be prepared, which are intended as an illustration onlyand not limiting of the scope of the invention.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1 Preparation of2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 1) Step 1a. Pent-4-yn-1-amine (Compound 0102)

To a solution of compound 0101 (6.0 g, 28.14 mmol) in a mixture solventsof methylene chloride and ethanol (10:1, 220 mL) was added hydrazinemonohydrate (14.1 g, 281.4 mmol). The reaction mixture was refluxed for5 hours and was then cooled and filtered. Water (200 mL) was added andthe pH was adjusted to 2 with 6N HCl. The mixture was stirred adequatelyand methylene chloride layer was separated. The aqueous layer wasadjusted to pH13 and was extracted with two portions of methylenechloride. The organic phase was collected and evaporated underatmosphere pressure to give the title product 0102 as a brown oil (4.4g) which was used directly to the next step without furtherpurification. LCMS: 84 [M+1]⁺.

Step 1b. 2,4-Dichloro-3-nitropyridine (Compound 0109)

Compound 0108 (10.0 g, 64.0 mmol) was dissolved in POCl₃ (70 mL) andheated overnight at 85° C. The excess POCl₃ was evaporated at atmospherepressure. The residuum was neutralized (pH7) with saturated NaHCO₃. Theprecipitate was filtered and dried to give the title compound 0109 as ayellow solid (9.95 g, 80.5%): ¹H NMR (CDCl₃) δ 7.47 (d, J=5.7 Hz, 1H),8.44 (d, J=5.1 Hz, 1H).

Step 1c. 2-Chloro-3-nitro-N-(pent-4-ynyl)pyridin-4-amine (Compound 0110)

To a solution of compound 0109 (8.9 g, 46.12 mmol) in DMF (177 mL) wasadded compound 0102 (5.8 g) and triethylamine (5.6 g, 55.34 mmol). Thereaction mixture was stirred at room temperature for 4 hours. Themixture was evaporated to remove DMF and purified by columnchromatography on silica gel (EtOAc/petroleum=10:1) to obtain the titlecompound 0110 as a yellow solid (8.6 g, 77.8%): LCMS: 240 [M+1]⁺; ¹H NMR(CDCl₃) δ 1.89 (m, 2H), 2.06 (t, J=2.7 Hz, 1H), 2.35 (m, 2H), 3.45 (m,2H), 6.63 (s, 1H), 6.69 (d, J=6.3 Hz, 1H), 8.04 (d, J=6.3 Hz, 1H).

Step 1d. 2-Chloro-N⁴-(pent-4-ynyl)pyridine-3,4-diamine (Compound 0111)

To a solution of compound 0110 (8.6 g, 35.88 mmol) in methanol (430 mL)was added water (43 mL), iron powder (20.04 g) and concentrated HClsolution (3 mL) The reaction mixture was stirred at room temperature for30 minutes and then heated to refluxed overnight. The mixture wasadjusted to pH11 with 6N NaOH and filtered and washed with methanol (50mL). The filtrate was concentrated and purified by column chromatographyon silica gel (EtOAc/petroleum=2:1) to obtain the title compound 0111 asa light yellow solid (5.5 g, 73.1%). LCMS: 210 [M+1]⁺; ¹H NMR (DMSO-d₆)δ 1.75 (m, 2H), 2.29 (m, 2H), 2.83 (t, J=2.7 Hz, 1H), 3.19 (m, 2H), 4.78(s, 2H) 5.73 (t, J=5.1 Hz, 1H) 6.41 (d, J=5.4 Hz, 1H), 7.41 (d, J=5.1Hz, 1H).

Step 1e. 4-Chloro-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridine-2(3H)-thione(Compound 0112)

A mixture of compound 0111 (3.64 g, 17.36 mmol), carbon disulfide (6.6g, 86.8 mmol), potassium hydroxide (4.87 g 86.8 mmol) in ethanol (22 mL)and water (3.3 mL) was heated to refluxed overnight. The mixture wascooled to room temperature and water (60 mL) was added. The mixture wasadjusted to pH7 with acetic acid and then extracted with methylenechloride (100 mL×2). The organic phase was concentrated at reducedpressure and purified by column chromatography on silica gel(EtOAc/petroleum at 5:1) to obtain the title compound 0112 as a lightyellow solid (3.9 g, 89%): LCMS: 252 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.91 (m,2H), 2.26 (m, 1H), 2.83 (t, J=2.7 Hz, 2H), 4.28 (t, J=7.5 Hz, 2H), 7.53(d, J=5.1 Hz, 1H), 8.15 (d, J=5.4 Hz, 1H), 13.64 (s, 1H).

Step 1f. 4-Amino-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridine-2(3H)-thione(Compound 0113)

A mixture of compound 0112 (1.0 g, 4.0 mmol) and sodium amide (3.0 g,77.0 mmol) in 25 mL liquid ammonia was charged in an air free sealedtube and stirred at 0° C. for 30 hours. The tube was opened after cooledto −40° C. and ethanol was added carefully to terminate the reactionuntil no gas generated. 200 mL of water was added and adjusted themixture to pH 7 with acetic acid and then extracted with two portions ofmethylene chloride. The combined organic phase was concentrated atreduced pressure and purified by column chromatography on silica gel(methylene chloride/methanol=50:1) to obtain the title compound 0113 asa grey solid (497 mg, 54%). LCMS: 233 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.89(m, 2H), 2.23 (m, 2H), 2.86 (s, 1H), 4.19 (t, J=7.5 Hz, 2H), 6.12 (s,2H), 6.75 (d, J=5.4 Hz, 1H), 7.74 (d, J=5.4 Hz, 1H), 12.50 (s, 1H).

Step 1g. 5-Bromo-6-iodobenzo[d][1,3]dioxole (Compound 0107-1)

A solution of compound 0106 (10.0 g, 50.0 mmol), anhydrous acetonitrile(150 mL), TFA (11.4 g, 100.0 mmol) and NIS (33.7 g, 150.0 mmol) wasstirred at room temperature for 24 h. The solvent was removed underreduce pressure and the crude purified by column chromatography onsilica gel (petroleum) to yield the title compound 0107-1 as a whitesolid (18.5 g, 91%): ¹H NMR (DMSO-d₆) δ 5.99 (s, 2H), 7.10 (s, 1H), 7.26(s, 1H).

Step 1h.2-(6-Bromobenzo[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 1)

A mixture of compound 0113 (150.0 mg, 0.65 mmol),5-Bromo-6-iodobenzo[d][1,3]dioxole (Compound 0107) (633.0 mg, 1.94mmol), neocuproine hydrate (13.0 mg, 0.065 mmol), CuI (12.0 mg, 0.065mmol) and NaOt-Bu (124.0 mg, 1.29 mmol) in anhydrous DMF (6 mL) wasstirred for 24 h at 110° C. (oil bath) under nitrogen atmosphere. Thesolvent was removed under high vacuum and the crude purified by columnchromatography on silica gel (CH₂Cl₂/MeOH=100/1) to obtain the titlecompound 1 as an orange solid (117 mg, 42%): m.p. 52.9˜60.5° C., LCMS:432 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.81 (m, 2H), 2.19 (m, 2H), 2.83 (t,J=2.4 Hz, 1H), 4.25 (t, J=7.2 Hz, 2H), 6.07 (s, 2H), 6.38 (s, 2H), 6.71(s 1H), 6.83 (d, J=6.0 Hz, 1H,), 7.35 (s, 1H), 7.72 (d, J=5.4 Hz, 1H).

Example 2 Preparation of2-(6-chlorobenzo[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 2) Step 2a. 5-Chloro-6-iodobenzo[d][1,3]dioxole (Compound0107)

A solution of compound 0106 (2.0 g, 12.77 mmol), acetonitrile (80 mL),TFA (2.9 g) and NIS (8.6 g, 38.3 mmol) was stirred at room temperaturefor 24 h. The solvent was removed under high vacuum and the crudeproduct was purified by column chromatography on silica gel (petroleum)to yield the title compound 0107 as a white solid (3.27 g, 90.6%): ¹HNMR (DMSO-d₆) δ 6.10 (s, 2H), 7.25 (s, 1H), 7.45 (s, 1H).

Step 2b.2-(6-Chlorobenzo[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 2)

A mixture of compound 0113 (100 mg, 0.43 mmol),5-Chloro-6-iodobenzo[d][1,3]dioxole (Compound 0107) (364 mg, 1.29 mmol),neocuproine hydrate (9 mg, 0.043 mmol), CuI (8 mg, 0.043 mmol) andNaO-t-Bu (83 mg, 0.86 mmol) in anhydrous DMF (4.6 mL) was stirred for 24h at 110° C. (oil bath) under nitrogen atmosphere. The solvent wasremoved under high vacuum and the crude purified by columnchromatography on silica gel (CH₂Cl₂/MeOH at 100/1) to obtain the titlecompound 1 as a light yellow solid (52 mg, 31%): LCMS: 387 [M+1]⁺; ¹HNMR (DMSO-d₆) δ 1.81 (m, 2H), 2.19 (m, 2H), 2.85 (t, 1H, J=2.4 Hz), 4.25(t, 2H, J=7.2 Hz), 6.09 (s, 2H), 6.37 (s, 2H), 6.76 (s 1H), 6.82 (d, 1H,J=5.7 Hz), 7.25 (s, 1H), 7.71 (d, 1H, J=5.7 Hz).

Example 3 Preparation of2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 3) Step 3a. 5,6-Diiodobenzo[d][1,3]dioxole (Compound 0107)

A solution of compound 0106 (1.0 g, 8.19 mmol), acetonitrile (51 mL),TFA (1.867 g) and NIS (4.05 g, 18.02 mmol) was stirred at roomtemperature for 24 h. The solvent was removed under high vacuum and thecrude product purified by column chromatography on silica gel(petroleum) to yield the title compound 0107 as a white solid (1.48 g,48%): ¹H NMR (DMSO-d₆) δ 6.05 (s, 2H), 7.46 (s, 2H).

Step 3b.2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 3)

A mixture of compound 0113 (200 mg, 0.86 mmol),5,6-Diiodobenzo[d][1,3]dioxole (Compound 0107) (483 mg, 1.29 mmol),neocuproine hydrate (18 mg, 0.086 mmol), CuI (16 mg, 0.086 mmol) andNaO-t-Bu (83 mg, 0.86 mmol) in anhydrous DMF (8 mL) was stirred for 24 hat 110° C. (oil bath) under nitrogen atmosphere. The solvent was removedunder high vacuum and the crude purified by column chromatography onsilica gel (CH₂Cl₂/MeOH at 100/1) to obtain the title compound 3 as awhite solid (82 mg, 20%): LCMS: 479 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.81 (m,2H), 2.20 (m, 2H), 2.84 (t, 1H, J=2.4 Hz), 4.23 (t, 2H, J=7.2 Hz), 6.05(s, 2H), 6.37 (s, 2H), 6.69 (s 1H), 6.82 (d, 1H, J=6.0 Hz), 7.48 (s,1H), 7.72 (d, 1H, J=5.7 Hz).

Example 3 (Method 2) Preparation of2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 3) Step 3a′.2-Chloro-N-(4-methoxybenzyl)-3-nitropyridin-4-amine (Compound 0201)

To a solution of compound 0109 (1 g, 5.18 mmol) in was in DMF (8.6 mL)was added (4-methoxyphenyl)methanamine (0.71 g, 5.18 mmol) andtriethylamine (0.644 mL). The solution was stirred at room temperaturefor 2 h. The mixture was evaporated to remove DMF. The resulting mixturewas purified by column chromatography on silica gel (EtOAc/petroleum at10:1) to obtain the title compound 0201 as a yellow solid (1.32 g, 87%):LCMS: 294 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 3.72 (s, 3H), 4.40 (d, 2H, J=6.3Hz), 6.81 (d, 1H, J=5.7 Hz), 6.91 (d, 2H, J=9.0 Hz), 7.25 (d, 2H, J=8.4Hz), 7.95 (d, 1H, J=5.4 Hz), 8.02 (t, 1H, J=5.7 Hz).

Step 3b′. 2-Chloro-N⁴-(4-methoxybenzyl)pyridine-3,4-diamine (Compound0202)

To a mixture of compound 0201(1.32 g, 4.49 mmol) in methanol (66 mL) andwater (6.6 mL) was added iron powder (2.51 g, 44.9 mmol) andconcentrated HCl solution (1 mL). The mixture was stirred at roomtemperature for 30 min, and then at reflux overnight. The mixture wasadjusted to pH 11 with 6N NaOH and filtered. The precipitate was washedwith methanol (10 mL). The combined filtrate and wash solution wasconcentrated and purified by column chromatography on silica gel(EtOAc/petroleum at 2:1) to obtain the title compound 0202 as a lightgreen solid (712 mg, 60%): LCMS: 264 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 3.73 (s,3H), 4.31 (d, 2H, J=5.7 Hz), 4.81 (s, 2H), 6.33 (m, 2H), 6.90 (d, 2H,J=8.7 Hz), 7.26 (d, 2H, J=9.0 Hz), 7.34 (d, 1H, J=5.1 Hz).

Step 3c′.4-Chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridine-2(3H)-thione(Compound 0203)

A mixture of 0202 (2 g, 7.6 mmol), carbon disulfide (2.88 g, 37.9 mmol),potassium hydroxide (2.12 g, 37.9 mmol) in ethanol (11.5 mL) and water(1.5 mL) was heated at reflux overnight. Water (100 mL) was added afterthe mixture was allowed to cool down to room temperature. The mixturewas adjusted to pH 7 with acetic acid and then extracted with twoportions of methylene chloride. The organic layer was collected andconcentrated at reduced pressure to leave an residue which was purifiedby column chromatography on silica gel (EtOAc/petroleum at 5:1) toobtain the title compound 0203 as a white solid (2 g, 86%): LCMS: 306[M]⁺; ¹H NMR (DMSO-d₆) δ 3.68 (s, 3H), 6.41 (s, 2H), 6.86 (d, 2H, J=8.7Hz), 7.36 (m, 3H), 8.07 (d, 1H, J=5.4 Hz), 13.74 (s, 1H).

Step 3d′.4-Amino-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridine-2(3H)-thione(Compound 0204)

A mixture of 0203 (1 g, 3.25 mmol) and sodium amide (3 g, 77 mmol) in 25mL liquid ammonia was charged in an air free sealed tube. The mixturewas then stirred at room temperature for 30 h. The mixture was cooled to−40° C. and then tube was opened. Ethanol was added carefully toterminate the reaction until no gas generated. Water (200 mL) was addedand the mixture was adjusted to pH 7 with acetic acid. The resultingsolid was filtered to obtain crude product which was purified by columnchromatography on silica gel (methylene chloride/methanol at 50:1) toobtain the title compound 0204 as a white solid (718 mg, 77%): LCMS: 287[M]⁺; ¹H NMR (DMSO-d₆) δ 3.68 (s, 3H), 5.31 (s, 2H), 6.06 (s, 2H), 6.59(d, 1H, J=6.3 Hz), 6.85 (d, 2H, J=9.0 Hz), 7.33 (d, 2H, J=8.4 Hz), 7.64(d, 1H, J=5.7 Hz), 12.53 (s, 1H).

Step 3e′2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0205-3)

A mixture of 0204 (725 mg, 2.53 mmol), 5,6-Diiodobenzo[d][1,3]dioxole(0107) (1.89 g, 5.06 mmol), neocuproine hydrate (53 mg, 0.253 mmol), CuI(48 mg, 0.253 mmol) and NaOt-Bu (365 mg, 3.80 mmol) in anhydrous DMF (32mL) was stirred for 24 h at 110° C. (oil bath) under nitrogenatmosphere. The solvent was removed under high vacuum and the crudepurified by column chromatography on silica gel (CH₂Cl₂/MeOH at 100/1)to obtain the title compound 0205-3 as a brown solid (734 mg, 55%):LCMS: 533 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 3.69 (s, 3H), 5.35 (s, 2H), 6.01(s, 2H), 6.47 (s, 1H), 6.80 (d, 2H, J=9.0 Hz), 7.06 (d, 2H, J=8.7 Hz),7.41 (s, 1H).

Step 3f.2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-3)

A solution of compound 0205-3 (730 mg, 1.37 mmol) in TFA (4.8 mL) wasstirred for 2 h at 80° C. The TFA was then evaporated and the resultingoil was adjusted to pH 7 with saturated NaHCO₃. The resultingprecipitate was collected by filtration and further purified by columnchromatography on silica gel (CH₂Cl₂/MeOH at 30/1) to give the titlecompound 0206-3 as a yellow solid (526 mg, 93%): LCMS: 413 [M+1]⁺; ¹HNMR (DMSO-d₆) δ 6.09 (s, 2H), 6.73 (m, 3H), 7.03 (s, 1H), 7.52 (m, 2H),12.45 (s, 1H).

Step 3g′.2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 3)

A mixture of 0206-3 (1 g, 2.426 mmol), 5-chloropent-1-yne (373 mg, 3.639mmol) and Cs₂CO₃ (1.34 g, 4.124 mmol) in DMF (35 mL) was stirred at 85°C. for 4 h. DMF was evaporated under vacuum, and the residue waspurified by column chromatography on silica gel (methylenechloride/methanol at 100:1) to yield the title compound 3 as a whitesolid (564 mg, 49%): m. p. 142˜145° C. 479 [M+1]⁺; ¹H NMR (DMSO-d₆) δ1.81 (m, 2H), 2.20 (m, 2H), 2.85 (t, 1H, J=2.7 Hz), 4.23 (t, 2H, J=7.2Hz), 6.05 (s, 2H), 6.36 (s, 2H), 6.68 (s 1H), 6.81 (d, 1H, J=6.0 Hz),7.48 (s, 1H), 7.72 (d, 1H, J=5.7 Hz).

Example 4 Preparation of2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-pentyl-1H-imidazo[4,5-c]pyridin-4-amine(Compound 4)

A mixture of compound 0206 (200 mg, 0.485 mmol), 1-bromopentane (110 mg,0.728 mmol) and Cs₂CO₃ (268 mg, 0.825 mmol) in DMF (7 mL) was stirred at85° C. for 2 h. DMF was evaporated under vacuum and the residue waspurified by column chromatography on silica gel (methylenechloride/methanol at 100:1) to yield the title compound 4 as a whitesolid (40 mg, 17%): m. p. 155˜160° C. LCMS: 483 [M+1]⁺; ¹H NMR (DMSO-d₆)δ 0.783 (t, 3H, J=6.6 Hz), 1.22 (m, 4H), 1.58 (m, 2H), 4.15 (t, 2H,J=7.2 Hz), 6.04 (s, 2H), 6.39 (s, 2H), 6.66 (s, 1H), 6.79 (d, 1H, J=5.7Hz), 7.49 (s, 1H), 7.71 (d, 1H, J=6.0 Hz).

Example 5 Preparation of2-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 7) Step 5a. 6,7-Diiodo-2,3-dihydrobenzo[b][1,4]dioxine(Compound 0107-7)

To a solution of compound 0106 (R=H, n=1) (2 g, 14.7 mmol) inacetonitrile (60 ml) was added NIS (9.92 g, 44.1 mmol) followed byCF₃COOH (3.35 g, 29.4 mmol). The mixture was stirred at room temperatureovernight. The reaction mixture was concentrated and purified by columnchromatography on silica gel (Petroleum ether) to provide the titlecompound 0107-7 as a white solid (0.7 g, 12%): ¹H NMR (DMSO-d₆) δ 4.21(s, 4H), 7.34 (s, 2H).

Step 5b.2-(7-Iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 7)

A mixture of compound 0113 (150 mg, 0.65 mmol),6,7-Diiodo-2,3-dihydrobenzo[b][1,4]dioxine (0107-7) (Compound 0107) (500mg, 1.29 mmol), NaOt-Bu (93 mg, 0.97 mmol), neocuproine hydrate (13 mg,0.065 mmol) and CuI (12 mg, 0.065 mmol) in dry DMF (6 ml) was stirred at110° C. overnight. The mixture was concentrated and purified first bycolumn chromatography on silica gel (CH₂Cl₂/MeOH=100/1) and followed byprep-HPLC to give the title compound 7 as a white solid (45 mg, 14%):m.p. 110-118° C. ¹H NMR (DMSO-d₆) δ 1.88 (m, 2H), 2.25 (m, 2H), 2.85 (t,J=2.9 Hz, 1H), 4.24 (m, 4H), 4.36 (t, J=6.9 Hz, 2H), 6.92 (s, 1H), 7.29(d, J=7.5 Hz, 1H), 7.44 (s, 1H), 7.76 (d, J=6.6 Hz, 1H), 8.47 (s, 2H),13.01 (s, 1H).

Example 6 Preparation of2-(2,3-dihydrobenzofuran-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 9) Step 6a.4-Amino-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridine-2(3H)-thione(Compound 0205-9)

A mixture of compound 0204 (1.0 g, 3.5 mmol),5-iodo-2,3-dihydrobenzofuran (0.86 g, 3.5 mmol), neocuproine hydrate (73mg, 0.35 mmol), CuI (67 mg, 0.35 mmol) and NaOt-Bu (403 mg, 4.2 mmol) inanhydrous DMF (20 mL) was stirred for 24 h at 110° C. (oil bath) undernitrogen atmosphere. The solvent was removed under high vacuum and thecrude was purified by column chromatography on silica gel(CH₂Cl₂/MeOH=50/1) to give the title compound 0205-9 as a yellow solid(0.38 g, 27%): LCMS: 405 [M+1]⁺.

Step 6b.2-(2,3-Dihydrobenzofuran-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-9)

A mixture of compound 0205-9 (370 mg, 0.915 mmol) and trifluoroaceticacid (10 mL) was stirred at refluxing for 5 h. The solvent was removedand the residue was suspended in saturated aqueous NaHCO₃ solution. Theresulting solid was collected and dried to give the title compound0206-9 as a yellow solid (210 mg, 81%): LCMS: 285 [M+1]⁺.

Step 6c.2-(2,3-Dihydrobenzofuran-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4amine (Compound 9)

A mixture of compound 0206-9 (204 mg, 0.72 mmol), Cs₂CO₃ (469 mg, 1.44mmol), 5-chloropent-1-yne (111 mg, 1.08 mol) and anhydrous DMF (5 mL)was stirred for 2 h at 80° C. The solvent was removed under high vacuumand the crude purified by column chromatography on silica gel(CH₂Cl₂/MeOH=100/1) to give the title compound 9 as a pale yellow solid(41 mg, 16%): m.p. 150˜157° C., LCMS: 351 [M+1]⁺. ¹H NMR (DMSO-d₆ δ1.70) (m, 2H), 2.17 (m, 2H), 2.87 (t, J=2.7 Hz, 1H), 3.14 (t, J=8.7 Hz,2H), 4.22 (t, J=7.5 Hz, 2H), 4.52 (t, J=8.7 Hz, 2H), 6.31 (s, 2H), 6.77(m, 2H), 7.20 (dd, J₁=1.8 Hz, J₂=8.1 Hz, 1H), 7.33 (s, 1H), 7.65 (d,J=4.2 Hz, 1H).

Example 7 Preparation of2-(benzofuran-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 10) Step 7a.2-(Benzofuran-5-ylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0205-10)

A mixture of compound 0204 (1.0 g, 3.5 mmol), 5-iodobenzofuran (1.2 g,4.92 mmol), neocuproine hydrate (73 mg, 0.35 mmol), CuI (67 mg, 0.35mmol) and NaO-t-Bu (403 mg, 4.2 mmol) in anhydrous DMF (20 mL) wasstirred for 24 h at 110° C. (oil bath) under nitrogen atmosphere. Thesolvent was removed under high vacuum and the crude purified by columnchromatography on silica gel (CH₂Cl₂/MeOH=50/1) to give the titlecompound 0205-10 as a yellow solid (0.44 g, 31%): LCMS: 403 [M+1]⁺.

Step 7b. 2-(Benzofuran-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-10)

A mixture of compound 0205-10 (430 mg, 1.07 mmol) and trifluoroaceticacid (10 mL) was stirred under reflux for 5 h. The solvent was removedand the residue was suspended in saturated aqueous NaHCO₃ solution. Theresulting solid was collected and dried to give the title compound0206-10 as a yellow solid (270 mg, 89%): LCMS: 283 [M+1]⁺.

Step 7c.2-(Benzofuran-5-ylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 10)

A mixture of compound 0206-10 (270 mg, 0.96 mmol), Cs₂CO₃ (623 mg, 1.91mmol), 5-chloropent-1-yne (147 mg, 1.44 mol) and anhydrous DMF (10 mL)was stirred for 2 h at 80° C. The solvent was removed under high vacuumand the crude purified by column chromatography on silica gel(CH₂Cl₂/MeOH=100/1) to give the title compound 10 as a pale yellow solid(21 mg, 6%). LCMS: 349 [M+1]⁺. ¹H NMR (DMSO-d₆ δ 1.73 (m, 2H), 2.17 (m,2H), 2.87) (t, J=2.4 Hz, 1H), 4.25 (t, J=7.5 Hz, 2H), 6.32 (s, 2H), 6.78(d, J=5.7 Hz, 1H), 6.96 (d, J=1.5 Hz, 1H), 7.35 (dd, J₁=1.8 Hz, J₂=8.7Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.69 (d, J=5.4 Hz, 1H), 7.74 (d, J=1.8Hz, 1H), 8.04 (d, J=1.8 Hz, 1H).

Example 8 Preparation of2-(3-methoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 11)

A mixture of compound 0113 (300 mg, 1.29 mmol), 1-iodo-3-methoxybenzene(0103) (907 mg, 3.87 mmol), neocuproine hydrate (27 mg, 0.129 mmol), CuI(25 mg, 0.129 mmol) and NaOt-Bu (248 mg, 2.58 mmol) in anhydrous DMF (12mL) was stirred for 24 h at 110° C. (oil bath) under nitrogenatmosphere. The solvent was removed under high vacuum and the crudepurified by column chromatography on silica gel (CH₂Cl₂/MeOH=100/1) toobtain crude compound which was purified by preparative HPLC to give thetitle product 11 as a white solid (190 mg, 43.5%): m.p. 139.2˜140.6° C.,LCMS: 339 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.74 (m, 2H), 2.16 (m, 2H), 2.85(t, J=2.7 Hz, 1H), 3.72 (s, 3H), 4.24 (t, J=7.5 Hz, 2H), 6.39 (s, 2H),6.85 (m, 4H), 7.27 (t, J=7.8 Hz, 1H), 7.72 (d, J=6.0 Hz, 1H).

Example 9 Preparation of2-(2-iodo-5-methoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 12) Step 9a. 1,2-Diiodo-4-methoxybenzene (Compound 0104-12)

A mixture of compound 103 (2.0 g, 8.5 mmol), TFA (1.94 g) and NIS (5.74g, 25.5 mmol) in acetonitrile (60 mL) was stirred at room temperaturefor 24 h. The solvent was removed under high vacuum and the crudepurified by column chromatography on silica gel (petroleum ether) toyield the title compound 104-12 as a colorless liquid (1.2 g, 38%). ¹HNMR (DMSO-d₆) δ 3.75 (s, 3H), 6.77 (m, 1H), 7.49 (d, J=2.7 Hz, 1H),7.760 (d, J=8.7 Hz, 1H).

Step 9b.2-(2-Iodo-5-methoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 12)

A mixture of compound 0113 (230.0 mg, 0.99 mmol), compound 104-12 (535.0mg, 1.49 mmol), neocuproine hydrate (21.0 mg, 0.10 mmol), CuI (19.0 mg,0.10 mmol) and NaOt-Bu (95.0 mg, 1.0 mmol) in anhydrous DMF (9.2 mL) wasstirred for 24 h at 110° C. (oil bath) under nitrogen atmosphere. Thesolvent was removed under high vacuum and the crude purified by columnchromatography on silica gel (CH₂Cl₂/MeOH=100/1) to obtain the titlecompound 12 as a white solid (75 mg, 16.3%): m.p. 114.5˜115.2° C., LCMS:465 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.80 (m, 2H), 2.17 (m, 2H), 2.81 (t,J=2.1 Hz, 1H), 3.59 (s, 3H), 4.24 (t, J=7.2 Hz, 2H), 6.26 (d, J=2.4 Hz,1H) 6.45 (s, 2H), 6.68 (m 1H), 6.84 (d, J=5.7 Hz, 1H), 7.75 (d, J=7.2Hz, 1H), 7.77 (d, J=8.7 Hz, 1H).

Example 10 Preparation of2-(2-bromo-5-methoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 13) Step 10a. 1-Bromo-2-iodo-4-methoxybenzene (Compound0104-13)

Bromine (0.206 mL, 4.0 mmol) was added dropwise into a solution ofcompound 0103 (1.0 g, 3.20 mmol) in acetic acid (4.5 mL) with constantstirring overnight. Water (15 mL) was then added to the reactionmixture, and the product was extracted into hexane (3×7.5 mL). Thecombined organic layers were washed with 5% sodium sulfite (7.5 mL) andbrine (7.5 mL), dried over magnesium sulfite, filtered and concentratedto leave an oily solid which was purified by chromatography on silicagel (petroleum) to yield the title product 0104-13 as a colorless oil(0.5 g, 37%): ¹H NMR (CDCl₃) δ 3.769 (s, 3H), 6.77 (dd, 1H, J₁=3.0 Hz,J₂=8.7 Hz), 7.39 (d, 1H, J=3.0 Hz), 7.47 (d, 1H, J=9.0 Hz).

Step 10b.2-(2-Bromo-5-methoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 13)

A mixture of compound 0113 (174 mg, 0.75 mmol), compound 0104-13 (469mg, 1.5 mmol), neocuproine hydrate (16 mg, 0.075 mmol), CuI (14 mg,0.075 mmol) and NaOt-Bu (96 mg, 1.0 mmol) in anhydrous DMF (8 mL) wasstirred for 24 h at 110° C. (oil bath) under nitrogen atmosphere. Thesolvent was removed under high vacuum and the crude purified by columnchromatography on silica gel (CH₂Cl₂/MeOH at 100/1) to obtain the titlecompound 13 as a yellow solid (60 mg, 19%): LCMS: 417 [M+1]⁺; ¹H NMR(DMSO-d₆) δ 1.88 (m, 2H), 2.23 (m, 2H), 2.81 (t, 1H, J=2.4 Hz), 3.68 (s,3H), 4.39 (t, 2H, J=7.2 Hz), 6.71 (d, 1H, J=2.7 Hz), 6.91 (dd, 1H,J₁=2.7 Hz, J₂=9.3 Hz), 7.31 (d 1H, J=6.9 Hz), 7.65 (d, 1H, J=9.0 Hz),7.78 (d, 1H, J=7.2 Hz), 8.63 (s, 2H), 13.248 (s, 1H).

Example 11 Preparation of2-(2-chloro-5-methoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 14) Step 11a. 1-Chloro-2-iodo-4-methoxybenzene (Compound0104-14)

A solution of 0103 (1 g, 4.27 mmol) and NCS (2.25 g, 17.09 mmol) inanhydrous DMF (24 mL) was stirred at room temperature for 2.5 h. Afterreaction, the solvent was removed and the crude was purified by silicagel column purification (petroleum) to give the title product 0104-14 asa colorless oil (440 mg, 38%): ¹H NMR (DMSO-d₆) δ 3.76 (s, 3H), 7.00(dd, 1H, J₁=2.7 Hz, J₂=8.4 Hz), 7.47 (m, 2H).

Step 11b.2-(2-Chloro-5-methoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 14)

A mixture of compound 0113 (150 mg, 0.646 mmol), compound 0104-14 (260mg, 0.969 mmol), neocuproine hydrate (13 mg, 0.065 mmol), CuI (12 mg,0.065 mmol) and NaOt-Bu (62 mg, 0.646 mmol) in anhydrous DMF (6 mL) wasstirred for 24 h at 110° C. (oil bath) under nitrogen atmosphere. Thesolvent was removed under high vacuum and the crude purified by columnchromatography on silica gel (CH₂Cl₂/MeOH at 100/1) to obtain the titlecompound 14 as a white solid (25 mg, 10%). LCMS: 373 [M+1]⁺; ¹H NMR(DMSO-d₆) δ 1.80 (m, 2H), 2.16 (m, 2H), 2.83 (s, 1H), 3.62 (s, 3H), 4.26(t, 2H, J=7.2 Hz), 6.38 (d, 1H, J=2.1 Hz), 6.48 (s, 2H), 6.85 (d 1H,J=6.6 Hz), 6.91 (dd, 1H, J₁=1.8 Hz, J₂=7.8 Hz), 7.48 (d, 1H, J=9.9 Hz),7.74 (d, 1H, J=5.7 Hz).

Example 12 Preparation of2-(2-iodo-4,5-dimethoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 15) Step 12a. 1,2-Diiodo-4,5-dimethoxybenzene (Compound0104-15)

To a solution of 1,2-dimethoxybenzene (2 g, 14.5 mmol) in anhydrous DMF(60 mL) was added NCS (9.67 g, 43.4 mmol) followed by trifluoroaceticacid (3.3 g, 28.9 mmol). The reaction was stirred at room temperatureovernight. The solution was concentrated and purified by columnchromatography on silica gel (petroleum ether) to provide the titlecompound 0104-15 as a white solid (1.9 g, 34%): ¹H NMR (DMSO-d₆) δ 3.71(s, 6H), 7.31 (s, 2H).

Step 12b.2-(2-Iodo-4,5-dimethoxyphenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 15)

A mixture of 0113 (150 mg, 0.65 mmol), compound 0104-15 (503 mg, 1.29mmol), NaOt-Bu (93 mg, 0.97 mmol), neocuproine hydrate (13 mg, 0.065mmol), and CuI (12 mg, 0.065 mmol) in dry DMF (6 ml) was stirred at 110°C. overnight. The mixture was concentrated and first purified by columnchromatography on silica gel (CH₂Cl₂/MeOH=100/1) and then by prep-HPLCto give the title product 15 as a white solid (40 mg, 13%): m.p.134-140° C. ¹H NMR (DMSO-d₆) δ 1.88 (m, 2H), 2.26 (m, 2H), 2.86 (t,J=2.4 Hz, 1H), 3.67 (s, 3H), 3.80 (s, 3H), 4.37 (t, J=7.4 Hz, 2H), 7.13(s, 1H), 7.29 (d, J=6.9 Hz, 1H), 7.44 (s, 1H), 7.75 (d, J=6.3 Hz, 1H),8.42 (s, 2H), 13.13 (s, 1H).

Example 13 Preparation of4-(4-amino-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-2-ylthio)-5-iodobenzene-1,2-diol(Compound 16)

To a solution of compound 3 (120 mg, 0.251 mmol) in dichloromethane (24mL) was added dropwise the solution of BCl₃ in dichloromethane (0.755mL, 1M) at room temperature under nitrogen. The mixture was stirred for30 min. and methanol (50 mL) was added. The mixture was heated to refluxtemperature for 1 h. The reaction was evaporated and the resultingresidue was purified by pre-HPLC to obtain the title compound 16 as awhite solid (35 mg, 30%): m.p. 107˜115° C. LCMS: 467 [M+1]⁺; ¹H NMR(DMSO-d₆) δ 1.88 (m, 2H), 2.25 (m, 2H), 2.84 (t, 1H, J=2.1 Hz), 4.33 (t,2H, J=6.6 Hz), 6.81 (s, 1H), 7.27 (m, 2H), 7.75 (d, 1H, J=7.2 Hz), 8.48(s, 2H), 9.56 (s, 1H), 9.82 (s, 1H), 13.16 (s, 1H).

Example 14 Preparation of2-(5-methoxy-2-nitrophenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 17)

A mixture of compound 0113 (150 mg, 0.646 mmol),1-iodo-5-methoxy-2-nitrobenzene (199 mg, 0.713 mmol), neocuproinehydrate (13 mg, 0.065 mmol), CuI (12 mg, 0.065 mmol) and NaOt-Bu (62 mg,0.646 mmol) in anhydrous DMF (6 mL) was stirred for 24 h at 110° C. (oilbath) under nitrogen atmosphere. The solvent was removed under highvacuum and the crude purified by column chromatography on silica gel(CH₂Cl₂/MeOH at 100/1) to obtain target compound 17 as a light yellowsolid (60 mg, 24%): LCMS: 384 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.77 (m, 2H),2.14 (m, 2H), 2.73 (t, 1H, J=2.4 Hz), 3.69 (s, 3H), 4.24 (t, 2H, J=6.9Hz), 6.04 (d, 1H, J=2.4 Hz), 6.63 (s, 2H), 6.88 (d 1H, J=6.0 Hz), 7.07(dd, 1H, J₁=2.4 Hz, J₂=9.3 Hz), 7.78 (d, 1H, J=6.0 Hz), 8.37 (d, 1H,J=9.3 Hz).

Example 15 Preparation of2-(4-amino-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-2-ylthio)-4-methoxybenzonitrile(Compound 18)

The title compound 18 was prepared as a white solid (25 mg, 11%) fromcompound 0113 (150 mg, 0.646 mmol), 2-iodo-4-methoxybenzonitrile (251mg, 0.969 mmol), neocuproine hydrate (13 mg, 0.0646 mmol), CuI (12 mg,0.0646 mmol) and NaOt-Bu (62 mg, 0.646 mmol) in anhydrous DMF (6 mL)using a procedure similar to that described for compound 17 (Example14): LCMS: 364 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.84 (m, 2H), 2.20 (m, 2H),2.83 (t, 1H, J=2.7 Hz), 3.76 (s 3H), 4.29 (t, 2H, J=7.5 Hz), 6.41 (s,2H), 6.77 (s, 2H J=2.4 Hz), 6.86 (m, 1H), 7.08 (dd, 1H, J₁=2.4 Hz,J₂=9.0 Hz), 7.75 (m, 1H), 7.90 (d, 1H, J=8.1 Hz).

Example 16 Preparation of1-(2-(4-amino-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-2-ylthio)-4-methoxyphenyl)ethanone(Compound 19) Step 16a. 1-(2-Iodo-4-methoxyphenyl)ethanone (Compound0104-19)

Anhydrous AlCl₃ (1.284 g, 9.6 mmol) was added to the mixture of 0103(1.0 g, 4.28 mmol) and CS₂ (4 ml). The resulting mixture was heated atreflux (56° C.) and then Ac₂O (0.35 g, 3.42 mmol) was added slowly intothe mixture. The mixture was kept refluxing for 1.5 h. and then CS₂ wasremoved under reduce pressure. The black residue was poured toice-concentrated HCl, and extracted with ether three times. The extractwas washed with H₂O (100 ml×2), 10% NaOH (100 ml×2), and washed againwith water until the water layer was colorless. The organic layer wasthen washed with brine, dried over anhydrous NaSO₄ and evaporated. Thecrude product was purified by column chromatography on silica gel(AcOEt/petroleum=1:5) to give the title compound 0104-19 as a pale redoil (160 mg, 14%): ¹H NMR (CDCl₃) δ 2.60 (s, 3H), 3.83 (s, 3H), 6.92(dd, 1H, J₁=2.4 Hz, J₂=8.7 Hz), 7.51 (d, 1H, J=2.4 Hz), 7.58 (d, 1H,J=8.7 Hz).

Step 16b.1-(2-(4-Amino-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-2-ylthio)-4-methoxyphenyl)ethanone(Compound 19)

The title compound 19 was prepared as a yellow solid (78 mg, 31.7%) fromcompound 0113 (150 mg, 0.646 mmol), compound 0104-19 (160 mg, 0.579mmol), neocuproine hydrate (15 mg, 0.0715 mmol), CuI (14 mg, 0.0715mmol) and NaOt-Bu (69 mg, 0.715 mmol) in anhydrous DMF (6 mL) using aprocedure similar to that described for compound 17 (Example 14): LCMS:381 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.75 (m, 2H), 2.12 (m, 2H), 2.619 (s 3H),2.77 (t, 1H, J=2.4 Hz), 3.63 (s, 3H), 4.18 (t, 2H, J=7.2 Hz), 5.92 (d,1H, J=2.1 Hz), 6.49 (s, 2H), 6.85 (d 1H, J=6.0 Hz), 6.93 (dd, 1H, J₁=2.4Hz, J₂=8.4 Hz), 7.75 (d, 1H, J=6.0 Hz), 8.13 (d, 1H, J=8.4 Hz).

Example 17 Preparation of2-(5-fluoro-2-iodophenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 20) Step 17a.2-(5-Fluoro-2-iodophenylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0205-20)

A mixture of compound 0204 (286 mg, 1.01 mmol),4-fluoro-1,2-diiodobenzene (447 mg, 1.2 mmol), NaOt-Bu (96 mg, 1 mmol),neocuproine hydrate (21 mg, 0.1 mmol), and CuI (19 mg, 0.1 mmol) in dryDMF (9 mL) was stirred at 110° C. overnight. The mixture wasconcentrated and purified by column chromatography on silica gel(CH₂Cl₂/MeOH=100/1) to give the title compound 0205-20 as a white solid(260 mg, 51%): LCMS: 507 [M+1]⁺; ¹H NMR (DMSO-d₆): δ 3.68 (s, 3H), 5.40(s, 2H), 6.32 (dd, 1H, J₁=2.7 Hz, J₂=9.9 Hz), 6.56 (s, 2H), 6.75 (d, 2H,J=8.7 Hz), 6.85 (m, 1H), 6.90 (d, 1H, J=5.7 Hz), 7.07 (d, 2H, J=8.7 Hz),7.76 (d, 1H, J=5.7 Hz), 7.85 (m, 2H).

Step 17b. 2-(5-Fluoro-2-iodophenylthio)-1H-imidazo[4,5-c]pyridin-4-amine(compound 0206-20)

A mixture of compound 0205-20 (330 mg, 0.65 mmol), trifluoroacetic acid(3 mL) was stirred at reflux for 2 h. The solvent was removed and theresidue was suspended in saturated aqueous NaHCO₃ solution. Theresulting solid was collected and dried to give the title compound0206-20 as a white solid (250 mg, 98%): LCMS: 387 [M+1]⁺; ¹H NMR(DMSO-d₆): δ 6.91 (d, 2H, J=6.3 Hz), 6.96 (m, 1H), 7.09 (dd, 1H, J₁=3Hz, J₂=8.4 Hz), 7.56 (d, 1H, J=6.9 Hz), 7.85 (s, 2H), 7.92 (m, 1H).

Step 17c.2-(5-Fluoro-2-iodophenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 20)

A mixture of compound 0206-20 (100 mg, 0.26 mmol), Cs₂CO₃ (169 mg, 0.52mmol), 5-chloropent-1-yne (40 mg, 0.39 mmol) and anhydrous DMF (5 mL)was stirred for 24 h at 80° C. The solvent was removed under high vacuumand the crude product was purified by column chromatography on silicagel (CH₂Cl₂/MeOH=20/1) to give the crude product as a pale white solidwhich was further purified by prep-HPLC to give the title compound 20 asa white solid (15 mg, 13%): LCMS: 453 [M+1]⁺; ¹H NMR (DMSO-d₆): δ 2.04(m, 2H), 2.18 (t, 2H, J=7.2 Hz), 2.80 (s, 1H), 4.26 (t, 2H, J=7.5 Hz),6.48 (s, 2H), 6.61 (dd, 1H, J₁=3 Hz, J₂=9.6 Hz,), 6.86 (d, 1H, J=6 Hz),6.94 (m, 1H), 7.76 (d, 1H, J=6 Hz), 7.93 (s, 2H).

Example 18 Preparation of2-(4,5-difluoro-2-iodophenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 21) Step 18a.2-(4,5-Difluoro-2-iodophenylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0205-21)

The title compound 0205-21 was prepared (130 mg 14%) from compound 0204(500 mg, 1.75 mmol), 1,2-difluoro-4,5-diiodobenzene (1277 mg, 3.49mmol), NaOt-Bu (251 mg, 2.62 mmol), neocuproine hydrate (36 mg, 0.175mmol), and CuI (33 mg, 0.175 mmol) in dry DMF (12 mL) using a proceduresimilar to that described for compound 0205-20 (Example 17): LCMS: 525[M+1]⁺.

Step 18b.2-(4,5-Difluoro-2-iodophenylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-21)

The title compound 0206-21 was prepared (140 mg, 76%) from compound0205-21 (240 mg, 0.46 mmol) and CF₃COOH (4 mL) using a procedure similarto that described for compound 0206-20 (Example 17): LCMS: 405 [M+1]⁺.

Step 18c.2-(4,5-Difluoro-2-iodophenylthio)-1-(pent-4-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 21)

The title compound 21 was prepared (25 mg, 18%) from compound0206-21(120 mg, 0.30 mmol), 5-chloropent-1-yne (46 mg, 0.45 mmol),Cs₂CO₃ (164 mg, 0.50 mmol) and KI (5 mg) in DMF (5 mL) using a proceduresimilar to that described for compound 20 (Example 17): m.p: 105-110° C.LCMS: 471 [M+1]⁺. 1H NMR: (DMSO-d₆) δ 1.83 (m, 2H), 2.19 (m, 2H), 2.83(t, J=2.7 Hz, 1H), 4.25 (t, J=7.2 Hz, 2H), 6.43 (s, 2H), 6.84 (d, J=5.7Hz, 1H), 7.05 (m, 1H), 7.73 (d, J=6.0 Hz, 1H), 8.06 (m, 1H).

Example 19 Preparation of2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1-(but-3-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 22) Step 19a.2-(6-Bromobenzo[d][1,3]dioxol-5-ylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0205-22)

The title compound 0205-22 was prepared as a brown solid (584 mg, 49%)from compound 0204 (700 mg, 2.44 mmol),5-bromo-6-iodobenzo[d][1,3]dioxole (1.20 g, 3.66 mmol), neocuproinehydrate (51 mg, 0.244 mmol), CuI (46 mg, 0.244 mmol) and NaOt-Bu (234mg, 2.44 mmol) in anhydrous DMF (31 mL) using a procedure similar tothat described for compound 0205-20 (Example 17): LCMS: 485 [M+1]⁺; ¹HNMR (DMSO-d₆) δ 3.69 (s, 3H), 5.35 (s, 2H), 6.04 (s, 2H), 6.54 (s, 1H),6.81 (m, 4H), 7.06 (d, 2H, J=8.7 Hz), 7.29 (s, 1H).

Step 19b.2-(6-Bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-22)

The title compound 0206-22 was prepared as a yellow solid (308 mg, 74%)from compound 0205-22 (557 mg, 1.15 mmol) and TFA (4 mL) using aprocedure similar to that described for compound 0206-20 (Example 17):LCMS: 365 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 6.07 (s, 2H), 6.58 (s, 2H), 6.69(d, 1H, J=6.0 Hz), 6.98 (s, 1H), 7.34 (s, 1H), 7.47 (d, 1H, J=6.0 Hz).

Step 19c.2-(6-Bromobenzo[d][1,3]dioxol-5-ylthio)-1-(but-3-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 22)

A solution of 0206-22 (200 mg, 0.548 mmol), PPh₃ (287 mg, 1.10 mmol),but-3-yn-1-ol (50 mg, 0.712 mmol), DIAD (332 mg, 1.644 mmol) in toluene(4 mL) and CH₂Cl₂ (1 mL) was stirred at room temperature for 20 min. Thesolvent was removed under vacuum and the crude purified by columnchromatography on silica gel (CH₂Cl₂/MeOH at 30/1) and followed bypre-HPLC to give the title product 22 as a white solid (82 mg, 36%): m.p. 154˜158° C. LCMS: 417 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 2.64 (m, 2H), 2.86(m, 1H), 4.38 (t, 2H, J=6.3 Hz), 6.07 (s, 2H), 6.40 (s, 2H), 6.66 (s,1H), 6.87 (d, 1H, J=5.7 Hz), 7.35 (s, 1H), 7.71 (d, 1H, J=5.4 Hz).

Example 20 Preparation of1-(but-3-ynyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 23)

The title compound 23 was prepared as a white solid (134 mg, 39.6%) fromcompound 0206-3 (300 mg, 0.727 mmol), PPh₃ (381 mg, 1.46 mmol),but-3-yn-1-ol (66 mg, 0.946 mmol), DIAD (441 mg, 2.18 mmol) in toluene(6 mL) and CH₂Cl₂ (1.5 mL) using a procedure similar to that describedfor compound 22 (Example 19): m. p. 201˜204° C. LCMS: 465 [M+1]⁺; ¹H NMR(DMSO-d₆) δ 2.73 (m, 2H), 2.92 (t, 1H, J=2.7 Hz), 4.50 (t, 2H, J=6.6Hz), 6.10 (s, 2H), 6.97 (s, 1H), 7.37 (d, 1H, J=6.6 Hz), 7.52 (s, 1H),7.76 (d, 1H, J=9.0 Hz), 8.58 (d, 2H, J=8.7 Hz), 13.29 (s, 1H).

Example 21 Preparation of2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1-(hex-5-ynyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 24)

The title compound 24 was prepared as a white solid (67 mg, 27%) fromcompound 0206-22 (200 mg, 0.548 mmol), PPh₃ (287 mg, 1.10 mmol),hex-5-yn-1-ol (70 mg, 0.712 mmol), DIAD (332 mg, 1.643 mmol) in toluene(5 mL) and CH₂Cl₂ (1.5 mL) using a procedure similar to that describedfor compound 22 (Example 19): LCMS: 445 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.44(m, 2H), 1.78 (m, 2H), 2.17 (m, 2H), 2.77 (t, 1H, J=2.7 Hz), 4.32 (t,2H, J=6.9 Hz), 6.13 (s, 2H), 7.02 (s, 1H), 7.30 (d, 1H, J=6.6 Hz), 7.42(s, 1H), 7.75 (d, 1H, J=6.6 Hz), 8.54 (s, 2H), 13.26 (s, 1H).

Example 22 Preparation of1-(hex-5-ynyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 25)

The title compound 25 was prepared as a white solid (90 mg, 25%) fromcompound 0206-3 (300 mg, 0.727 mmol), PPh₃ (381 mg, 1.46 mmol),hex-5-yn-1-ol (93 mg, 0.946 mmol), DIAD (441 mg, 2.18 mmol) in toluene(6 mL) and CH₂Cl₂ (1.5 mL) using a procedure similar to that describedfor compound 22 (Example 19): m. p. 158˜162° C. LCMS: 493 [M+1]⁺; ¹H NMR(DMSO-d₆) δ 1.45 (m, 2H), 1.77 (m, 2H), 2.18 (m, 2H), 2.77 (t, 1H, J=2.7Hz), 4.31 (t, 2H, J=7.2 Hz), 6.10 (s, 2H), 7.00 (s, 1H), 7.31 (d, 1H,J=7.5 Hz), 7.54 (s, 1H), 7.75 (d, 1H, J=7.2 Hz), 8.56 (d, 2H, J=8.7 Hz),13.25 (s, 1H).

Example 23 Preparation of4-(4-amino-2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butanenitrile(Compound 26) Step 23a.2-(2-Iodo-5-methoxyphenylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0205-26)

The title compound 0205-26 was prepared as a brown solid (734 mg, 55%)from compound 0204 (1 g, 3.5 mmol), 1,2-diiodo-3-methoxybenzene (1.5 g,4.2 mmol), neocuproine hydrate (73 mg, 0.35 mmol), CuI (66 mg, 0.35mmol) and NaOt-Bu (335 mg, 3.5 mmol) in anhydrous DMF (33 mL) using aprocedure similar to that described for compound 0205-20 (Example 17):LCMS: 519[M+1]⁺.

Step 23b.2-(2-Iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-26)

The title compound 0206-26 was prepared as a yellow solid (181 mg, 53%)from compound 0205-26 (443 mg, 0.85 mmol) and TFA (4 mL) using aprocedure similar to that described for compound 0206-20 (Example 17):LCMS: 399 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 3.61 (s, 3H), 6.72 (m, 5H), 7.51(d, 1H, J=6.3 Hz), 7.74 (d, 1H, J=8.7 Hz).

Step 23c.4-(4-Amino-2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butanenitrile(Compound 26)

A mixture of compound 0206-26 (150 mg, 0.38 mmol), 4-bromobutanenitrile(83.6 mg, 0.565 mmol), Cs₂CO₃ (208 mg, 0.64 mmol) in DMF (5 mL) wasstirred at 80° C. for 2 h. The mixture was evaporated to remove DMF andpurified first by column chromatography on silica gel (CH₂Cl₂/MeOH at100/1) and then by pre-HPLC to yield the title compound 26 as a whitesolid (20 mg, 11.3%): m. p. 146˜150° C. LCMS: 466 [M+1]⁺; ¹H NMR(DMSO-d₆) δ 1.95 (m, 2H), 2.54 (m, 2H), 3.59 (s, 3H), 4.24 (t, 2H, J=7.5Hz), 6.31 (d, 1H, J=3.3 Hz), 6.48 (s, 2H), 6.69 (dd, 1H, J₁=2.7 Hz,J₂=8.7 Hz), 6.85 (d, 1H, J=6.0 Hz), 7.77 (m, 2H).

Example 24 Preparation of4-(4-amino-2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butanenitrile(Compound 27)

The title compound 27 was prepared as a light yellow solid (43 mg, 24%)from compound 0206-22 (150 mg, 0.411 mmol), 4-bromobutanenitrile (91 mg,0.616 mmol), Cs₂CO₃ (227 mg, 0.699 mmol) in DMF (6 mL) using a proceduresimilar to that described for compound 26 (Example 23): m. p. 140˜149°C. LCMS: 432 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.96 (m, 2H), 2.56 (t, 2H, J=7.2Hz), 4.25 (t, 2H, J=7.8 Hz), 6.08 (s, 2H), 6.39 (s, 2H), 6.70 (s, 1H),6.83 (d, 1H, J=8.4 Hz), 7.36 (s, 1H), 7.73 (d, 1H, J=5.7 Hz).

Example 25 Preparation of4-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butanenitrile(Compound 28)

The title compound 28 was prepared as a white solid (82 mg, 39%) fromcompound 0206-3 (180 mg, 0.437 mmol), 4-bromobutanenitrile (97 mg, 0.655mmol), Cs₂CO₃ (241 mg, 0.743 mmol) in DMF (6.3 mL) using a proceduresimilar to that described for compound 26 (Example 23): m. p. 210˜222°C. LCMS: 480 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 2.05 (m, 2H), 2.62 (t, 2H, J=7.2Hz), 4.36 (t, 2H, J=7.2 Hz), 6.10 (s, 2H), 7.00 (s, 1H), 7.30 (d, 1H,J=7.5 Hz), 7.53 (s, 1H), 7.77 (d, 1H, J=6.9 Hz), 8.52 (s, 2H), 13.07 (s,1H).

Example 26 Preparation of5-(4-amino-2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)pentanenitrile(Compound 29)

The title compound 29 was prepared as a light yellow solid (68 mg, 37%)from compound 0206-22 (150 mg, 0.411 mmol), 5-bromopentanenitrile (100mg, 0.616 mmol), Cs₂CO₃ (227 mg, 0.699 mmol) in DMF (6 mL) using aprocedure similar to that described for compound 26 (Example 23): m. p.133˜135° C. LCMS: 446 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.51 (m, 2H), 1.73 (m,2H), 2.50 (m, 2H), 4.21 (t, 2H, J=6.6 Hz), 6.07 (s, 2H), 6.38 (s, 2H),6.69 (s, 1H), 6.84 (d, 1H, J=7.5 Hz), 7.36 (s, 1H), 7.72 (d, 1H, J=6.0Hz).

Example 27 Preparation of5-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)pentanenitrile(Compound 30)

The title compound 30 was prepared as a white solid (92 mg, 48%) fromcompound 0206-3 (162 mg, 0.393 mmol), 5-bromopentanenitrile (96 mg,0.590 mmol), Cs₂CO₃ (217 mg, 0.668 mmol) in DMF (5.7 mL) using aprocedure similar to that described for compound 26 (Example 23): m. p.179˜191° C. LCMS: 494 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.58 (m, 2H), 1.80 (m,2H), 2.53 (m, 2H), 4.33 (t, 2H, J=6.6 Hz), 6.10 (s, 2H), 7.02 (s, 1H),7.33 (d, 1H, J=7.5 Hz), 7.54 (s, 1H), 7.77 (d, 1H, J=7.2 Hz), 8.55 (s,2H), 13.21 (s, 1H).

Example 28 Preparation of1-(2-aminoethyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 32) Step 28a.2-(2-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethyl)isoindoline-1,3-dione(Compound 0302-32)

A mixture of compound 0206-3 (500 mg, 1.2 mmol),2-(2-bromoethyl)isoindoline-1,3-dione (457 mg, 1.8 mmol) and Cs₂CO₃ (672mg, 2.1 mmol) in anhydrous DMF (8 mL) was stirred at 50° C. for 4 h. Thereaction mixture was cooled to room temperature and filtered. Thefiltrate was evaporated under high vacuum to give a crude product as anorange solid which was purified by column chromatography on silica gel(CH₂Cl₂/MeOH=100/1) to provide the title compound 0302-32 as a paleyellow solid (390 mg, 56%): LC-MS: 586 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆)δ 3.92 (t, 2H, J=5.3 Hz), 4.50 (t, 2H, J=5.3 Hz), 6.00 (s, 2H), 6.38 (s,2H), 6.49 (s, 1H), 6.75 (d, 1H, J=6.0 Hz), 7.19 (s, 1H), 7.64 (d, 1H,J=6.0 Hz), 7.73 (m, 4H).

Step 28b.1-(2-Aminoethyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 32)

A mixture of compound 0302-32 (5 g, 8.55 mmol) and N₂H₄-H₂O (4.28 g,85.5 mmol) in CH₂Cl₂ (150 mL) and EtOH (15 mL) was stirred at 50° C. for2 h. The solid was removed by filtration and the filtrate was washedwith brine (100 mL×2), dried over Na₂SO₄, filtered and evaporated togive the title compound 32 as a white solid (3 g, 77%): m. p. 111˜121°C. LC-MS: 456 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.46 (s, 2H) 2.80 (t,2H, J=6.3 Hz), 4.16 (t, 2H, J=6.6 Hz), 6.05 (s, 2H), 6.29 (s, 2H), 6.69(s, 1H), 6.84 (d, 1H, J=6.0 Hz), 7.46 (s, 1H), 7.70 (d, 1H, J=5.7 Hz).

Example 29 Preparation of2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 33) Step 29a.2-(2-(4-Amino-2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethyl)isoindoline-1,3-dione(Compound 0302-33)

The title compound 0302-33 was prepared as a pale yellow solid (720 mg,50%) from compound 0206-22 (975 mg, 2.67 mmol),2-(2-bromoethyl)isoindoline-1,3-dione (1.017 g, 4.00 mmol), Cs₂CO₃(1.475 g, 4.54 mmol) in anhydrous DMF (38 mL) using a procedure similarto that described for compound 0302-32 (Example 28): LCMS: 538 [M+1]⁺.

Step 29b.1-(2-Aminoethyl)-2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0303-33)

The title compound 0303-33 was prepared as a pale yellow solid (495 mg,91%) from compound 0302-33 (720 mg, 1.337 mmol) and N₂H₄-H₂O (886 mg,14.71 mmol) in CH₂Cl₂ (27 mL) and EtOH (3 mL) using a procedure similarto that described for compound 0303-32 (Example 28): LCMS: 408 [M+1]⁺.

Step 29c.2-(6-Bromobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 33)

To a solution of compound 0303-33 (150 mg, 0.613 mmol) in methanol (10mL) was added pivalaldehyde (63 mg, 0.736 mmol). After the mixture wasstirred for 30 min at room temperature, NaBH₃CN (154 mg, 2.452 mmol) wasadded slowly, and the mixture was stirred for additional 30 min. Thereaction was terminated by adding saturated NaHCO₃ (10 mL) and theresulting mixture was diluted with water (100 mL) and extracted withdichloromethane (50×2). The combined organic layer was concentrated toleave a residue which was purified by pre-HPLC to give the titlecompound 33 as a white solid (60 mg, 20%): m.p. 181˜187° C. LCMS: 478[M+1]⁺; ¹H NMR (DMSO-d₆) δ 0.76 (s, 9H), 1.61 (s, 1H), 2.18 (s, 2H),2.76 (t, 2H, J=6.3 Hz), 4.24 (t, 2H, J=6.3 Hz), 6.06 (s, 2H), 6.31 (s,2H), 6.62 (s, 1H), 6.83 (d, 1H, J=5.7 Hz), 7.34 (s, 1H), 7.70 (d, 1H,J=5.7 Hz).

Example 30 Preparation of2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 34)

The title compound 34 was prepared as a white solid (2.718 g, 26%) fromcompound 32 (9.1 g, 19.9 mmol), pivalaldehyde (2.06 g, 24 mmol) andNaBH₃CN (5.027 g, 80 mmol) using a procedure similar to that describedfor compound 33 (Example 29): m.p. 203˜207° C. LCMS: 526 [M+1]⁺; ¹H NMR(DMSO-d₆) δ 0.77 (s, 9H), 1.60 (s, 1H), 2.18 (s, 2H), 2.75 (t, 2H, J=5.7Hz), 4.23 (t, 2H, J=5.4 Hz), 6.04 (s, 2H), 6.33 (s, 2H), 6.58 (s, 1H),6.83 (d, 1H, J=6.0 Hz), 7.46 (s, 1H), 7.77 (d, 1H, J=5.7 Hz).

Example 30 (Method 2) Preparation of2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 34) Step 30a′.2-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethylacetate (Compound 0402-34)

A mixture of compound 0206-3 (300 mg, 0.728 mmol), 2-bromoethyl acetate(182 mg, 1.092 mmol) and Cs₂CO₃ (402 mg, 1.24 mmol) in DMF (10 mL) wasstirred at 85° C. for 2 h. DMF was evaporated under vacuum and theresidue was purified by column chromatography on silica gel (methylenechloride/methanol at 100:1) to yield the title compound 0402-34 as awhite solid (188 mg, 50.4%): LCMS: 499 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.86(s, 3H), 4.26 (t, 2H, J=4.8 Hz), 4.45 (t, 2H, J=4.8 Hz), 6.03 (s, 2H),6.35 (s, 2H), 6.68 (s, 1H), 6.81 (d, 1H, J=6.0 Hz), 7.76 (s, 1H), 7.71(d, 1H, J=6.0 Hz).

Step 30b′.2-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethanol(Compound 0403-34)

A suspension of compound 0402-34 (180 mg, 0.36 mmol) in MeOH (3 mL) wastreated with K₂CO₃ (60 mg, 0.43 mmol) at 50° C. for 1 h. The mixture wasdiluted with water (15 mL) and filtered to provide the title compound0403-34 as a white solid (150 mg, 91%): LCMS: 457 [M+1]⁺; ¹H NMR(DMSO-d₆) δ 3.63 (m, 2H), 4.27 (t, 2H, J=5.4 Hz), 4.98 (t, 2H, J=5.7Hz), 6.05 (s, 2H), 6.31 (s, 2H), 6.69 (s, 1H), 6.80 (d, 1H, J=6.0 Hz),7.46 (s, 1H), 7.69 (d, 1H, J=5.7 Hz).

Step 30c′.2-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethylmethanesulfonate (Compound 0404-34)

Compound 0403-34 (133 mg, 0.292 mmol) was dissolved in hot anhydrousdioxane (4 mL). The solution was cooled to 40° C. and was then treatedwith NEt₃ (89 mg, 0.876 mmol) and MsCl (50 mg, 0.438 mmol) for 20 min.The mixture was concentrated and purified by column chromatography onsilica gel (CH₂Cl₂/MeOH=50/1) to provide the title compound 0404-34 as awhite solid (122 g, 78.3%): LCMS: 535 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 3.07(s, 3H), 4.46 (t, 2H, J=4.5 Hz), 4.59 (t, 2H, J=5.1 Hz), 6.05 (s, 2H),6.59 (s, 2H), 6.71 (s, 1H), 6.90 (d, 1H, J=6.0 Hz), 7.48 (s, 1H), 7.73(d, 1H, J=6.6 Hz).

Step 30d′.2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 34)

A mixture of compound 0404-34 (170 mg, 0.318 mmol)2,2-dimethylpropan-1-amine hydrochloride (786 mg, 6.36 mmol) and K₂CO₃(1.318 g, 9.54 mmol) in toluene (10 mL) was heated at 60° C. for 1 h.the solvent was removed and the crude was purified by columnchromatography on silica gel (CH₂Cl₂/MeOH=40/1) and followed pre-HPLC toprovide the title compound 34 as a pale yellow solid (25 mg, 15%): m.p.193˜201° C. LCMS: 526 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 0.77 (s, 9H), 1.60 (s,1H), 2.18 (s, 2H), 2.75 (t, 2H, J=5.7 Hz), 4.23 (t, 2H, J=5.4 Hz), 6.04(s, 2H), 6.33 (s, 2H), 6.58 (s, 1H), 6.83 (d, 1H, J=6.0 Hz), 7.46 (s,1H), 7.77 (d, 1H, J=5.7 Hz).

Example 31 Preparation of2-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 37) Step 31a.2-(7-Iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0205-37)

The title compound 0205-37 was prepared as a brown solid (2.2 g, 38%)from compound 0204 (3 g, 10.5 mmol),6,7-Diiodo-2,3-dihydrobenzo[b][1,4]dioxine (0107-7) (8.1 g, 21 mmol),neocuproine hydrate (0.2 g, 1.05 mmol), CuI (0.2 g, 1.05 mmol) andNaOt-Bu (1.5 g, 15.7 mmol) in anhydrous DMF (100 mL) using a proceduresimilar to that described for compound 0205-20 (Example 17): LCMS:547[M+1]⁺; ¹H NMR (DMSO-d₆) δ 3.69 (s, 3H), 4.19 (m, 4H), 5.49 (s, 2H),6.68 (s, 1H), 6.83 (d, 2H, J=8.4 Hz), 7.11 (d, 2H, J=8.7 Hz), 7.28 (d,1H, J=7.2 Hz), 7.35 (s, 1H), 7.71 (d, 1H, J=7.2 Hz), 8.42 (s, 2H), 13.36(s, 1H).

Step 31b.2-(7-Iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-37)

The title compound 0206-37 was prepared as a yellow solid (1.5 g, 88%)from compound 0205-37 (2.2 g, 4 mmol) was dissolved in TFA (20 mL) usinga procedure similar to that described for compound 0206-20 (Example 17):LCMS: 427 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 4.29 (m, 4H), 6.96 (d, 1H, J=6.9Hz), 7.20 (s, 1H), 7.50 (s, 1H), 7.63 (d, 1H, J=6.9 Hz), 8.42 (s, 2H),13.36 (s, 1H).

Step 31c.2-(2-(4-Amino-2-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethyl)isoindoline-1,3-dione(Compound 0302-37)

The title compound 0302-37 was prepared as a white solid (1.2 g, 57%)from compound 0206-37 (1.5 g, 3.5 mmol),2-(2-bromoethyl)isoindoline-1,3-dione (1.34 g, 5.3 mmol), Cs₂CO₃ (1.94g, 6.0 mmol) and DMF (50 mL) using a procedure similar to that describedfor compound 0302-32 (Example 28): LCMS: 600 [M+1]⁺; ¹H NMR (DMSO-d₆) δ3.92 (t, 2H, J=5.7 Hz), 4.16 (m, 4H), 4.48 (t, 2H, J=4.8 Hz), 6.38 (s,2H), 6.41 (s, 1H), 6.75 (d, 1H, J=6 Hz), 7.15 (s, 1H), 7.64 (d, 1H,J=5.7 Hz), 7.77 (m, 4H).

Step 31d.1-(2-Aminoethyl)-2-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0303-37)

The title compound 0303-37 was prepared as a pale yellow solid (790 mg,84%) from compound 0302-37 (1.2 g, 2 mmol) and N₂H₄—H₂O (1 g, 20 mmol)in CH₂Cl₂ (28 mL) and EtOH (3 mL) using a procedure similar to thatdescribed for compound 0303-32 (Example 28): LC-MS: 470 [M+1]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 1.51 (m, 2H), 2.77 (t, 2H, J=6.6 Hz), 4.16 (m, 6H),6.27 (s, 2H), 6.53 (s, 1H), 6.81 (d, 1H, J=6 Hz), 7.35 (s, 1H), 7.67 (d,1H, J=5.7 Hz).

Step 31e.2-(7-Iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 37)

The title compound 37 was prepared as a white solid (128 mg, 14%) fromcompound 0303-37 (790 mg, 1.7 mmol), pivalaldehyde (217 mg, 2.5 mmol)and NaBH₃CN (423 mg, 6.7 mmol) using a procedure similar to thatdescribed for compound 33 (Example 29): m.p. 193˜200° C. LCMS: 540[M+1]⁺; ¹H NMR (DMSO-d₆) δ 0.793 (s, 9H), 2.32 (s, 2H), 2.88 (t, 2H,J=6.3 Hz), 4.18 (m, 4H), 4.32 (t, 2H, J=6.6 Hz), 6.50 (s, 1H), 6.76 (s,2H), 6.94 (d, 1H, J=6 Hz), 7.37 (s, 1H), 7.73 (d, 1H, J=6.3 Hz).

Example 32 Preparation of1-(2-(tert-butylamino)ethyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 40)

A solution of compound 0404-34 (250 mg, 0.47 mmol) in tert-butylamine(30 mL) was stirred at 60° C. for 24 h in a pressure vessel. The solventwas removed and the crude was purified by column chromatography onsilica gel (CH₂Cl₂/MeOH=50/1) and followed by pre-HPLC to provide thetitle compound 40 as a white solid (34 mg, 15%): m.p. 194˜197° C. LCMS:512 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 0.88 (s, 9H), 1.60 (s, 1H), 2.70 (t,J=6.0 Hz, 2H), 4.20 (t, J=6.0 Hz, 2H), 6.05 (s, 2H), 6.35 (s, 2H), 6.70(s, 1H), 6.83 (d, J=6.0 Hz, 1H), 7.48 (s, 1H), 7.72 (d, J=6.0 Hz, 1H).

Example 33 Preparation of2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(isopropylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 42)

The title compound 42 was prepared as a white solid (40 mg, 17%) fromcompound 0404-34 (252 mg, 0.47 mmol) in isopropylamine (30 mL) using aprocedure similar to that described for compound 40 (Example 32): m.p.170˜172° C. LCMS: 498 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 0.86 (d, J=6.3 Hz, 6H),1.68 (s, 1H), 2.62 (m, 1H), 2.74 (t, J=6.6 Hz, 2H), 4.21 (t, J=6.6 Hz,2H), 6.04 (s, 2H), 6.36 (s, 2H), 6.67 (s, 1H), 6.82 (d, J=6.0 Hz, 1H),7.47 (s, 1H), 7.71 (d, J=6.0 Hz, 1H).

Example 34 Preparation of2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(pentan-3-ylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 44)

To a solution of compound 32 (228 mg, 0.5 mmol) in methanol (9 mL) wasadded 3-pentanone (65 mg, 0.75 mmol). After the reaction was stirred for30 min at room temperature, NaBH₃CN (125 mg, 2 mmol) was added slowly.Trace of CH₃COOH was added and the mixture was stirred for overnight.The reaction was terminated by adding saturated NaHCO₃ (20 mL). Themixture was diluted with water (100 mL) and extracted withdichloromethane (50 mL×3). The extract was concentrated and purified bypre-HPLC to give the title compound 44 as a white solid (139 mg, 53%):m.p. 142˜147° C. LCMS: 526 [M+1]⁺; ¹H NMR (DMSO-d₆): δ 0.75 (t, J=6.6Hz, 6H), 1.31 (m, 4H), 2.42 (m, 1H), 2.85 (t, J=7.2 Hz, 2H), 4.33 (t,J=7.2 Hz, 2H), 6.06 (s, 2H), 6.52 (s, 2H), 6.66 (s, 1H), 6.92 (d, J=6.3Hz, 1H), 7.49 (s, 1H), 7.74 (d, J=6.0 Hz, 1H).

Example 35 Preparation of1-(2-(dimethylamino)ethyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 46)

To a solution of compound 32 (150 mg, 0.32 mmol) in methanol (6 mL) wasadded aqueous HCHO solution (52 mg, 0.64 mmol). After stirred for 30 minat room temperature, NaBH₃CN (81 mg, 1.28 mmol) was added slowly, andthe mixture was stirred overnight. The reaction was terminated by addingsaturated NaHCO₃ (10 ml). The mixture was diluted with water (100 ml)and extracted with dichloromethane (50 mL×2). The extract wasconcentrated and purified by pre-HPLC to give the title compound 46 (30mg, 19%) as a white solid. m.p. 170˜172° C.; LCMS: 484[M+1]⁺; ¹H NMR(DMSO-d₆): δ 2.14 (s, 6H), 2.48 (t, J=6.3 Hz, 2 H), 4.27 (t, J=6.3 Hz,2H), 6.05 (s, 2H), 6.38 (s, 2H), 6.67 (s, 1H), 6.81 (d, J=6.0 Hz, 1H),7.48 (s, 1H), 7.72 (d, J=6.0 Hz, 1H).

Example 36 Preparation of 2-(6-iodobenzodioxol-5-ylthio)-1-(2-(methylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 48)

The title compound 48 was prepared as a white solid (40 mg, 18%) fromcompound 0404-34 (250 mg, 0.47 mmol) in methylamine alcoholic solution(30 mL) using a procedure similar to that described for compound 40(Example 32): m.p. 145˜155° C. LCMS: 470 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.85(s, 1H), 2.23 (s, 6H), 2.73 (t, J=6.6 Hz, 2H), 4.24 (t, J=6.6 Hz, 2H),6.05 (s, 2H), 6.34 (s, 2H), 6.68 (s, 1H), 6.82 (d, J=6.0 Hz, 1H), 7.47(s, 1H), 7.71 (d, J=6.0 Hz, 1H).

Example 37 Preparation of 2-(2-iodo-5-methoxyphenylthio)-1-(2(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 50)Step 37a.2-(2-(4-Amino-2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethyl)isoindoline-1,3-dione(Compound 0302-50)

The title compound 0302-50 was prepared as a white solid (315 mg, 44%)from compound2-(2-Iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-26) (500 mg, 1.256 mmol),2-(2-bromoethyl)isoindoline-1,3-dione (478 mg, 1.884 mmol) and Cs₂CO₃(694 mg, 2.135 mmol) in anhydrous DMF (18 mL) using a procedure similarto that described for compound 0302-32 (Example 28): LCMS: 572 [M+1]⁺.

Step 37b.1-(2-Aminoethyl)-2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0303-50)

The title compound 0303-50 was prepared as a white solid. (206 mg, 86%)from compound 0302-50 (310 mg, 0.543 mmol) and N₂H₄—H₂O (320 mg, 5.43mmol) in CH₂Cl₂ (10 mL) and EtOH (2 mL) using a procedure similar tothat described for compound 0303-32 (Example 28): LCMS: 442 [M+1]⁺.

Step 37c.2-(2-Iodo-5-methoxyphenylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 50)

The title compound 50 was prepared as a white solid (45 mg, 28%) fromcompound 0303-50 (140 mg, 0.317 mmol), pivalaldehyde (33 mg, 0.381 mmol)and NaBH₃CN (80 mg, 1.268 mmol) using a procedure similar to thatdescribed for compound 33 (Example 29): m.p. 155˜167° C. LCMS: 512[M+1]⁺; ¹H NMR (DMSO-d₆) δ 0.76 (s, 9H), 2.15 (s, 2H), 2.74 (t, 2H,J=6.3 Hz), 3.58 (s, 3H), 4.22 (t, 2H, J=6.3 Hz), 6.30 (d, 1H, J=2.4 Hz),6.43 (s, 2H), 6.67 (dd, 1H, J₁=3.0 Hz, J₂=9.0 Hz), 6.85 (d, 1H, J=6.07Hz), 7.74 (m, 2H).

Example 38 Preparation of2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 51) Step 38a.3-(4-Amino-2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propylacetate (Compound 0402-51)

A mixture of compound 0206-22 (500 mg, 1.37 mmol), 3-bromopropyl acetate(372 mg, 2.05 mmol) and Cs₂CO₃ (757 mg, 2.33 mmol) in DMF (17 mL) wasstirred at 85° C. for 2 h. DMF was evaporated under vacuum and theresidue was purified by column chromatography on silica gel (methylenechloride/methanol at 100:1) to yield the title compound 0402-51 as awhite solid (340 mg, 53%): LCMS: 465 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.92 (m,5H), 3.94 (t, 2H, J=5.7 Hz), 4.27 (t, 2H, J=6.9 Hz), 6.07 (s, 2H), 6.39(s, 2H), 6.64 (s, 1H), 6.80 (d, 1H, J=6.0 Hz), 7.36 (s, 1H), 7.72 (d,1H, J=5.7 Hz).

Step 38b.3-(4-Amino-2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propan-1-ol(Compound 0403-51)

A suspension of compound 0402-51 (340 mg, 0.73 mmol) in MeOH (7 mL) wastreated with K₂CO₃ (122 mg, 0.88 mmol) at 50° C. for 1 h. The mixturewas diluted with water (25 mL) and filtered to provide the titlecompound 0403-51 as a white solid (264 mg, 85%): LCMS: 423 [M+1]⁺; ¹HNMR (DMSO-d₆) δ 1.78 (m, 2H), 3.39 (m, 2H), 4.24 (t, 2H, J=7.2 Hz), 4.65(t, 2H, J=4.8 Hz), 6.08 (s, 2H), 6.35 (s, 2H), 6.67 (s, 1H), 6.80 (d,1H, J=5.7 Hz), 7.36 (s, 1H), 7.71 (d, 1H, J=6.0 Hz).

Step 38c.3-(4-Amino-2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propylmethanesulfonate (0404-51)

Compound 0403-51 (264 mg, 0.624 mmol) was dissolved in hot anhydrousdioxane (8.6 mL). The solution was cooled to 40° C. and was treated withNEt₃ (189 mg, 1.87 mmol) and MsCl (107 mg, 0.935 mmol) for 20 min. Themixture was concentrated and purified by column chromatography on silicagel (CH₂Cl₂/MeOH=50/1) to give the title compound 0404-51 as a whitesolid (143 g, 50%): LCMS: 501 [M+1]⁺.

Step 38d.2-(6-Bromobenzo[d][1,3]dioxol-5-ylthio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 51)

A solution of compound 0404-51 (113 mg, 0.225 mmol) in isopropylamine (5mL) was stirred at 60° C. for 1 h in a pressure vessel. The solvent wasremoved and the crude was purified by column chromatography on silicagel (CH₂Cl₂/MeOH=40/1) to provide the title compound 51 as a white solid(31 mg, 30%): m.p. 140˜149° C. LCMS: 464 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.05(m, 6H), 1.91 (m, 2H), 2.67 (t, 2H, J=7.2 Hz), 2.89 (m, 1H), 4.27 (t,2H, J=7.5 Hz), 6.08 (s, 2H), 6.38 (s, 2H), 6.68 (s, 1H), 6.88 (d, 1H,J=5.7 Hz), 7.37 (s, 1H), 7.73 (d, 1H, J=6.0 Hz).

Example 39 Preparation of2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 52) Step 39a.3-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propylacetate (Compound 0402-52)

The title compound 0402-52 was prepared as a white solid (310 mg, 50%)from compound2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-3) (500 mg, 1.213 mmol), 3-bromopropyl acetate (329 mg,1.819 mmol) and Cs₂CO₃ (670 mg, 2.062 mmol) in DMF (17 mL) using aprocedure similar to that described for compound 0402-51 (Example 38).

Step 39b.3-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propan-1-ol(Compound 0403-52)

The title compound 0403-52 was prepared as a white solid (250 mg, 88%)from compound 0402-52 (310 mg, 0.605 mmol) and K₂CO₃ (100 mg, 0.727mmol) in MeOH (5 mL) using a procedure similar to that described forcompound 0403-51 (Example 38): LCMS: 471 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.78(m, 2H), 3.39 (m, 2H), 4.22 (t, 2H, J=6.9 Hz), 4.64 (t, 2H, J=4.8 Hz),6.05 (s, 2H), 6.33 (s, 2H), 6.66 (s, 1H), 6.79 (d, 1H, J=6.0 Hz), 7.48(s, 1H), 7.71 (d, 1H, J=5.7 Hz).

Step 39c.3-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propylmethanesulfonate (Compound 0404-52)

The title compound 0404-52 was prepared as a white solid (181 g, 62%)from compound 0403-52 (250 mg, 0.532 mmol), NEt₃ (161 mg, 1.596 mmol)and MsCl (91 mg, 0.798 mmol) using a procedure similar to that describedfor compound 0404-51 (Example 38): LCMS: 549 [M+1]⁺; ¹H NMR (DMSO-d₆) δ2.08 (m, 2H), 3.16 (s, 3H), 4.25 (m, 4H), 6.05 (s, 2H), 6.39 (s, 2H),6.67 (s, 1H), 6.82 (d, 1H, J=5.7 Hz), 7.48 (s, 1H), 7.73 (d, 1H, J=5.7Hz).

Step 39d.2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 52)

The title compound 52 was prepared as a white solid (54 mg, 32%) fromcompound 0404-52 (180 mg, 0.328 mmol) in isopropylamine (5 mL) using aprocedure similar to that described for compound 51 (Example 38): m.p.185˜193° C. LCMS: 512 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 0.97 (m, 6H), 1.81 (m,2H), 2.55 (m, 2H), 2.73 (m, 1H), 4.24 (t, 2H, J=6.3 Hz), 6.05 (s, 2H),6.38 (s, 2H), 6.65 (s, 1H), 6.84 (d, 1H, J=5.4 Hz), 7.48 (s, 1H), 7.72(d, 1H, J=5.7 Hz).

Example 40 Preparation of2-(2-bromo-5-methoxyphenylthio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 53) Step 40a.2-(2-Bromo-5-methoxyphenylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0205-53)

A mixture of compound 0204 (1.549 g, 5.41 mol),1-bromo-2-iodo-4-methoxybenzene (Compound 0104-13) (2.54 g, 8.115 mol),neocuproine hydrate (113 mg, 0.541 mmol), CuI (103 mg, 0.541 mmol) andNaOt-Bu (519 mg, 5.41 mmol) in anhydrous DMF (50 mL) was stirred for 24h at 110° C. (oil bath) under nitrogen atmosphere. The solvent wasremoved under high vacuum and the crude purified by columnchromatography on silica gel (CH₂Cl₂/MeOH at 100/1) to give the titlecompound 0205-53 as a brown solid (1.67 g, 65%): LCMS: 471 [M+1]⁺.

Step 40b.2-(2-Bromo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-53)

Compound 0205-53 (1.67 g, 3.55 mmol) was dissolved in TFA (12 mL) andstirred for 2 h at 80° C. The solvent was evaporated and the residue wasadjusted to pH 7 with saturated NaHCO₃. The resulting precipitate wascollected by filtration and further purified by column chromatography onsilica gel (CH₂Cl₂/MeOH at 30/1) to give the title compound 0206-53 as ayellow solid (1.105 g, 88%): LCMS: 351 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 3.65(s, 3H), 6.78 (m, 3H), 7.08 (s, 2H), 7.55 (m, 2H).

Step 40c.3-(4-Amino-2-(2-bromo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propylacetate (Compound 0402-53)

The title compound 0402-53 was prepared as a light yellow solid (750 mg,53%) from compound 0206-53 (1.105 g, 3.15 mmol), 3-bromopropyl acetate(855 mg, 4.72 mmol) and Cs₂CO₃ (1.74 g, 5.35 mmol) in DMF (57 mL) usinga procedure similar to that described for compound 0402-51 (Example 38):LCMS: 451 [M+1]⁺.

Step 40d.3-(4-Amino-2-(2-bromo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propan-1-ol(Compound 0403-53)

The title compound 0403-53 was prepared as a white solid (560 mg, 82%)from compound 0402-53 (750 mg, 1.66 mmol) and K₂CO₃ (276 mg, 1.99 mmol)in MeOH (13 mL) using a procedure similar to that described for compound0403-51 (Example 38): LCMS: 409 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.78 (m, 2H),3.37 (m, 2H), 3.61 (s, 3H), 4.25 (t, 2H, J=7.2 Hz), 4.63 (t, 1H, J=5.4Hz), 6.32 (d, 1H, J=3.0 Hz), 6.44 (s, 2H), 6.83 (m, 2H), 7.60 (d, 1H,J=9.0 Hz), 7.74 (d, 1H, J=5.7 Hz).

Step 40e.3-(4-Amino-2-(2-bromo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propylmethanesulfonate (Compound 0404-53)

The title compound 0404-52 was prepared as a white solid (300 g, 47%)from compound 0403-53 (560 mg, 1.368 mmol), NEt₃ (415 mg, 4.105 mmol)and MsCl (235 mg, 2.052 mmol) using a procedure similar to thatdescribed for compound 0404-51 (Example 38): LCMS: 487 [M+1]⁺.

Step 40f.2-(2-Bromo-5-methoxyphenylthio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine(53)

The title compound 53 was prepared as a white solid (54 mg, 32%) fromcompound 0404-53 (300 mg, 0.639 mmol) in isopropylamine (20 mL) using aprocedure similar to that described for compound 51 (Example 38): m.p.125˜129° C. LCMS: 450 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 0.89 (d, 6H, J=5.4 Hz),1.51 (s, 1H), 1.74 (m, 2H), 2.38 (t, 2H, J=6.9 Hz), 2.55 (m, 1H), 3.60(s, 3H), 4.24 (t, 2H, J=7.2 Hz), 6.33 (d, 1H, J=2.4 Hz), 6.46 (s, 2H),6.84 (m, 2H), 7.60 (d, 1H, J=8.7 Hz), 7.72 (d, 1H, J=5.4 Hz).

Example 41 Preparation of2-(2-iodo-5-methoxyphenylthio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 54) Step 41a.2-(2-Iodo-5-methoxyphenylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0205-54)

The title compound 0205-54 was prepared as a brown solid (734 mg, 55%)from compound 0204 (1 g, 3.5 mmol), 1,2-Diiodo-4-methoxybenzene(Compound 0104-12) (1.5 g, 4.2 mmol), neocuproine hydrate (73 mg, 0.35mmol), CuI (66 mg, 0.35 mmol) and NaOt-Bu (335 mg, 3.5 mmol) inanhydrous DMF (33 mL) using a procedure similar to that described forcompound 0205-53 (Example 40): LCMS: 519[M+1]⁺.

Step 41b.2-(2-Iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-54)

The title compound 0206-54 was prepared as a yellow solid (181 mg, 53%)from compound 0205-54 (443 mg, 0.85 mmol) and TFA (4 mL) using aprocedure similar to that described for compound 0206-53 (Example 40):LCMS: 399 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 3.61 (s, 3H), 6.72 (m, 5H), 7.51(d, 1H, J=6.3 Hz), 7.74 (d, 1H, J=8.7 Hz).

Step 41c.3-(4-Amino-2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propylacetate (Compound 0402-54)

The title compound 0402-54 was prepared as a light yellow solid (531 mg,53%) from compound 0206-54 (800 mg, 2.01 mmol), 3-bromopropyl acetate(546 mg, 3.02 mmol) and Cs₂CO₃ (1.11 g, 3.42 mmol) in DMF (36 mL) usinga procedure similar to that described for compound 0402-51 (Example 38):LCMS: 499 [M+1]⁺.

Step 41d.3-(4-Amino-2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propan-1-ol(Compound 0403-54)

The title compound 0403-54 was prepared as a white solid (412 mg, 85%)from compound 0402-54 (531 mg, 1.066 mmol) and K₂CO₃K₂CO₃ (177 mg, 1.279mmol) in MeOH (8.3 mL) using a procedure similar to that described forcompound 0403-51 (Example 38): LCMS: 457 [M+1]⁺.

Step 41e.3-(4-Amino-2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propylmethanesulfonate (Compound 0404-54)

The title compound 0404-53 was prepared as a white solid (260 mg, 54%)from compound 0403-54 (412 mg, 0.905 mmol), NEt₃ (275 mg, 2.716 mmol)and MsCl (156 mg, 1.358 mmol) using a procedure similar to thatdescribed for compound 0404-51 (Example 38): LCMS: 535 [M+1]⁺.

Step 41f.2-(2-Iodo-5-methoxyphenylthio)-1-(3-(isopropylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 54)

The title compound 54 was prepared as a white solid (18 mg, 16%) fromcompound 0404-54 (120 mg, 0.225 mmol) in isopropylamine (20 mL) using aprocedure similar to that described for compound 51 (Example 38): LCMS:498 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 0.91 (d, 6H, J=6.3 Hz), 1.75 (m, 2H),2.43 (t, 2H, J=5.7 Hz), 2.59 (m, 1H), 3.58 (s, 3H), 4.23 (t, 2H, J=7.2Hz), 6.32 (d, 1H, J=2.7 Hz), 6.44 (s, 2H), 6.68 (dd, 1H, J₁=3.0 Hz,J₂=9.0 Hz), 6.85 (d, 1H, J=6.3 Hz), 7.75 (m, 2H).

Example 42 Preparation of2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(3-(neopentylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 56) Step 42a.2-(3-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propyl)isoindoline-1,3-dione(Compound 0302-56)

The title compound 0302-56 was prepared as a pale yellow solid (410 mg,57%) from compound2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-3) (500 mg, 1.2 mmol),2-(3-bromopropyl)isoindoline-1,3-dione (610 mg, 2.4 mmol) and Cs₂CO₃(652 mg, 2.0 mmol) in anhydrous DMF (8.5 mL) using a procedure similarto that described for compound 0302-32 (Example 28): LC-MS: 599.7[M+1]⁺; ¹H NMR (DMSO-d₆): δ 1.93 (m, 2H), 3.61 (t, J=6.6 Hz, 2H), 4.21(t, J=8.1 Hz, 2H), 6.04 (s, 2H), 6.40 (s, 2H), 6.50 (s, 1H), 6.87 (d,J=6.0 Hz, 1H), 7.21 (s, 1H), 7.70 (d, J=6.0 Hz, 1H), 7.85 (s, 4H).

Step 42b.1-(3-Aminopropyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0303-56)

The title compound 0303-56 was prepared as a pale yellow solid (200 mg,74%) from compound 0302-56 (350 mg, 0.58 mmol) and N₂H₄—H₂O (580 mg,11.6 mmol) in CH₂Cl₂ (7.0 mL) and EtOH (0.6 mL) using a proceduresimilar to that described for compound 0303-32 (Example 28): LC-MS:469.7 [M+1]⁺.

Step 42c.2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1-(3-(neopentylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 56)

The title compound 56 was prepared as a white solid (110 mg, 37%) fromcompound 0303-56 (257 mg, 0.55 mmol) and pivalaldehyde (60 mg, 0.70mmol) using a procedure similar to that described for compound 33(Example 29): m.p. 170˜174° C. LCMS: 540 [M+1]⁺; ¹H NMR (DMSO-d₆): δ0.84 (s, 9H), 1.76 (m, 2H), 2.14 (s, 2H), 2.43 (t, J=6.9 Hz, 2H), 4.23(t, J=7.2 Hz, 2H), 6.04 (s, 2H), 6.36 (s, 2H), 6.63 (s, 1H), 6.80 (d,J=6.0 Hz, 1H), 7.47 (s, 1H), 7.71 (d, J=6.0 Hz, 1H).

Example 43 Preparation of1-(3-(tert-butylamino)propyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 58)

The title compound 58 was prepared as a white solid (64 mg, 37%) fromcompound3-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propylmethanesulfonate (0404-52) (180 mg, 0.328 mmol) in tert-butylamine (20mL) using a procedure similar to that described for compound 51 (Example38): m.p. 224˜227° C. LCMS: 526 [M+1]⁺; ¹H NMR (DMSO-d₆): δ 0.95 (s,9H), 1.71 (m, 2H), 2.38 (t, J=7.2 Hz, 2H), 4.23 (t, J=7.2 Hz, 2H), 6.04(s, 2H), 6.37 (s, 2H), 6.64 (s, 1H), 6.82 (d, J=6.0 Hz, 1H), 7.48 (s,1H), 7.72 (d, J=6.0 Hz, 1H).

Example 44 Preparation of2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(3-(pentan-3-ylamino)propyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 60)

To a solution of1-(3-Aminopropyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0303-56) (150 mg, 0.32 mmol) in methanol (6 mL) was added3-pentanone (33 mg, 0.38 mmol). After stirred for 30 min at roomtemperature, NaBH₃CN (80 mg, 1.28 mmol) was added slowly. Trace ofCH₃COOH was added and the mixture was stirred for overnight. Thereaction was terminated by adding saturated NaHCO₃ (10 mL). The mixturewas diluted with water (100 mL) and extracted with dichloromethane (50mL×2). The extract was concentrated and purified by pre-HPLC to give thetitle compound 60 as a white solid (34 mg, 20%): m.p. 164˜166° C. LCMS:540 [M+1]⁺; ¹H NMR (DMSO-d₆): δ 0.80 (s, 9H), 1.29 (m, 4H), 2.21 (m,1H), 2.43 (t, J=6.3 Hz, 2H), 4.24 (t, J=6.9 Hz, 2H), 6.05 (s, 2H), 6.40(s, 2H), 6.64 (s, 1H), 6.83 (d, J=5.7 Hz, 1H), 7.49 (s, 1H), 7.72 (d,J=5.7 Hz, 1H).

Example 45 Preparation of2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1-(2-isopropoxyethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 61)

A solution of2-(6-bromobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(compound 0206-22) (500 mg, 1.37 mmol), PPh₃ (718 mg, 2.74 mmol),2-isopropoxyethanol (185 mg, 1.78 mmol) and DIAD (830 mg, 4.11 mmol) intoluene (12 mL) and CH₂Cl₂ (3 mL) was stirred at room temperature for 20min. The solvent was removed under vacuum and the crude purified bycolumn chromatography on silica gel (CH₂Cl₂/MeOH at 30/1) and followedby pre-HPLC to give the title compound 61 as a white solid (113 mg,18%): m. p. 183˜190° C. LCMS: 451 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 0.94 (d,6H, J=5.4 Hz), 3.45 (m, 1H), 3.64 (t, 2H, J=7.5 Hz), 4.51 (t, 2H, J=3.9Hz), 6.12 (s, 2H), 7.02 (s, 1H), 7.28 (d, 1H, J=7.5 Hz), 7.40 (s, 1H),7.74 (d, 1H, J=6.6 Hz), 8.57 (s, 2H), 13.28 (s, 1H).

Example 46 Preparation of2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1-(2-isopropoxyethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 62)

The title compound 62 was prepared as a white solid (100 mg, 28%) fromcompound2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-3) (300 mg, 0.727 mmol), PPh₃ (381 mg, 1.46 mmol),2-isopropoxyethanol (98.5 mg, 0.946 mmol) and DIAD (441 mg, 2.18 mmol)in toluene (6 mL) and CH₂Cl₂ (1.5 mL) using a procedure similar to thatdescribed for compound 61 (Example 45): m. p. 195˜201° C. LCMS: 499[M+1]⁺; ¹H NMR (DMSO-d₆) δ 0.95 (d, 6H, J=6.6 Hz), 3.45 (m, 1H), 3.64(t, 2H, J=5.1 Hz), 4.49 (t, 2H, J=5.1 Hz), 6.09 (s, 2H), 6.99 (s, 1H),7.27 (d, 1H, J=6.9 Hz), 7.52 (s, 1H), 7.73 (d, 1H, J=7.5 Hz), 8.49 (s,2H), 13.12 (s, 1H).

Example 47 Preparation of2-(2-iodo-5-methoxyphenylthio)-1-(2-isopropoxyethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 64)

The title compound 64 was prepared as a white solid (20 mg, 8.2%) fromcompound 2-(2-iodo-5-methoxyphenylthio)-1H-imidazo[4,5-c]pyridin-4-amine(compound 0206-54) (200 mg, 0.50 mmol), PPh₃ (263 mg, 1.00 mmol),2-isopropoxyethanol (68 mg, 0.65 mmol) and DIAD (304 mg, 1.51 mmol) intoluene (5 mL) and CH₂Cl₂ (1 mL) using a procedure similar to thatdescribed for compound 61 (Example 45): m. p. 102˜108° C. LCMS: 485[M+1]⁺; ¹H NMR (DMSO-d₆) δ 0.89 (d, 6H, J=6.9 Hz), 3.38 (m, 1H), 3.56(t, 2H, J=5.4 Hz), 3.60 (s, 3H), 4.35 (t, 2H, J=4.5 Hz), 6.39 (m, 3H),6.67 (dd, 1H, J₁=2.1 Hz, J₂=8.1 Hz), 6.83 (d, 1H, J=6.0 Hz), 7.74 (m,2H).

Example 48 Preparation of4-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butanamide(Compound 66) Step 48a. Ethyl4-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butanoate(Compound 0502-66)

A mixture of2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-3) (200 mg, 0.485 mmol), ethyl 4-bromobutanoate (142 mg,0.728 mmol), Cs₂CO₃ (268 mg, 0.825 mmol) in DMF (7 mL) was stirred at85° C. for 2 h. DMF was evaporated under vacuum and the residue waspurified by column chromatography on silica gel (methylenechloride/methanol at 100:1) to yield the title compound 0502-66 as awhite solid (168 mg, 66%): LCMS: 527 [M+1]⁺.

Step 48b.4-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butanamide(Compound 66)

Compound 0502-66 (180 mg, 0.342 mmol) was dissolved in 5 mL ammonia inmethanol (40%, W/W) and the mixture was stirred at 50° C. in a sealedtube overnight. Solvent was evaporated under reduced pressure and theresidue was purified by column chromatography on silica gel (methylenechloride/methanol at 40:1) to yield the title compound 66 as a whitesolid (68 mg, 40%): m.p. 227˜232° C., LCMS: 498 [M+1]⁺; ¹H NMR (DMSO-d₆)δ 1.84 (m, 2H), 2.06 (t, 2H, J=7.2 Hz), 4.17 (t, 2H, J=7.2 Hz), 6.05 (s,2H), 6.39 (s, 2H), 6.68 (s, 1H), 6.81 (m, 2H), 7.28 (s, 1H), 7.47 (s,1H), 7.71 (d, 1H, J=6.0 Hz).

Example 49 Preparation of5-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)pentanamide(Compound 68) Step 49a. Methyl5-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)pentanoate (Compound 0502-68)

The title compound 0502-68 was prepared as a white solid (131 mg, 51%)from compound2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-3) (200 mg, 0.485 mmol), methyl 5-bromopentanoate (142mg, 0.728 mmol), Cs₂CO₃ (268 mg, 0.825 mmol) in DMF (8 mL) using aprocedure similar to that described for compound 0502-66 (Example 48):LCMS: 527 [M+1]⁺; ¹H NMR (DMSO-d₆) δ 1.47 (m, 2H), 1.63 (m, 2H), 2.28(t, 2H, J=7.5 Hz), 3.54 (s, 3H), 4.17 (t, 2H, J=6.9 Hz), 6.05 (s, 2H),6.38 (s, 2H), 6.66 (s, 1H), 6.80 (d, 1H, J=6.0 Hz), 7.48 (s, 1H), 7.71(d, 1H, J=5.7 Hz).

Step 49b.5-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)pentanamide(Compound 68)

The title compound 68 was prepared as a white solid (38 mg, 30%) fromcompound 0502-68 (131 mg, 0.249 mmol) and 10 mL ammonia in methanol(40%, W/W) using a procedure similar to that described for compound0502-66 (Example 48): m.p. 203˜210° C., LCMS: 512 [M+1]⁺; ¹H NMR(DMSO-d₆) δ 1.44 (m, 2H), 1.62 (m, 2H), 2.02 (t, 2H, J=7.2 Hz), 4.16 (t,2H, J=6.9 Hz), 6.06 (s, 2H), 6.52 (s, 2H), 6.70 (m, 2H), 6.84 (d, 1H,J=5.7 Hz), 7.23 (s, 1H), 7.49 (s, 1H), 7.71 (d, 1H, J=6.0 Hz).

Example 50 Preparation of6-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)hexanamide(Compound 70) Step 50a. Ethyl6-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)hexanoate(Compound 0502-70)

The title compound 0502-70 was prepared as a white solid (200 mg, 30%)from compound2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-3) (500 mg, 1.2 mmol), methyl ethyl 6-bromohexanoate (401mg, 1.8 mmol), Cs₂CO₃ (670 mg, 2.1 mmol) in DMF (18 mL) using aprocedure similar to that described for compound 0502-66 (Example 48):LCMS: 555 [M+1]⁺.

Step 50b.6-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)hexanamide(Compound 70)

The title compound 70 was prepared as a white solid (35 mg, 18%) fromcompound 0502-70 (200 mg, 0.36 mmol) and 28 mL ammonia in methanol (40%,W/W) using a procedure similar to that described for compound 0502-66(Example 48): m.p. 194˜198° C., LCMS: 526 [M+1]⁺; ¹H NMR (DMSO-d₆) δ1.20 (m, 2H) 1.41 (m, 2H), 1.57 (m, 2H), 1.96 (t, 2H, J=7.8 Hz), 4.14(t, 2H, J=7.4 Hz), 6.05 (s, 2H), 6.38 (s, 2H), 6.68 (2, 2H), 6.81 (d,1H, J=5.7 Hz), 7.19 (s, 1H), 7.48 (s, 1H), 7.71 (d, 1H, J=6.0 Hz).

Example 51 Preparation ofN-(2-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethyl)acetamide(Compound 72)

Compound 32 (200 mg, 0.44 mmol) and NEt₃ (0.1 ml, 0.66 mmol) wasdissolved in dichloromethane (10 ml) and cooled to 0° C. with ice-waterbath. To this cold solution was added acetyl chloride (38 mg, 0.48 mmol)dropwise. The solution was stirred at 0° C. for 0.5 h and then thesolvent was removed under reduced pressure. The residue was purified bypre-HPLC to give the title compound 72 as a white solid (47 mg, 22%):m.p. 193˜197° C., LC-MS: 498 [M+1]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 1.67(s, 3H), 3.32 (m, 2H), 4.21 (t, 2H, J=5.6 Hz), 6.02 (s, 2H), 6.29 (s,2H), 6.70 (s, 1H), 6.71 (d, 1H, J=5.7 Hz), 7.43 (s, 1H), 7.68 (d, 1H,J=5.7 Hz), 7.97 (t, 1H, J=6.0 Hz).

Example 52 Preparation ofN-(3-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)propyl)acetamide(Compound 74)

A suspension of1-(3-aminopropyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0303-56) (190 mg, 0.41 mmol) in acetic acid (1.4 mL) wascooled to 0° C. To this cold solution was added acetic anhydride (125mg, 1.23 mmol). The reaction mixture was allowed to warm to roomtemperature and stirred at room temperature overnight. The reactionmixture was diluted with CH₂Cl₂ (8 mL) and the solvent was removed underreduced pressure to leave a residue which was purified by pre-HPLC togive the title product 74 as a white solid (90 mg, 43%): m.p. 102˜104°C., LC-MS: 512.0 (M+H⁺). ¹H NMR (300 MHz, DMSO-d₆) δ 1.77 (m, 5H), 3.01(m, 2H), 4.16 (t, 2H, J=7.5 Hz), 6.05 (s, 2H), 6.36 (s, 2H), 6.62 (s,1H), 6.80 (d, 1H, J=5.7 Hz), 7.47 (s, 1H), 7.71 (d, 1H, J=6.0 Hz), 7.90(t, 1H, J=4.5 Hz).

Example 53 Preparation ofN-(4-(4-amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butyl)acetamide(Compound 76) Step 53a.2-(4-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butyl)isoindoline-1,3-dione(Compound 0302-76)

A mixture of2-(6-Iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-3) (412 mg, 1.0 mmol),2-(4-bromobutyl)isoindoline-1,3-dione (620 mg, 2.2 mmol), Cs₂CO₃ (814mg, 2.5 mmol) in anhydrous DMF (6 mL) was heated to 85° C. and stirredfor 2 h. The reaction mixture was cooled to room temperature andfiltered. The solvent DMF was removed under high vacuum to give a crudeproduct as an orange solid which was purified by column chromatographyon silica gel (CH₂Cl₂/MeOH/NEt₃=100/1/0.05) to give the title compound0302-76 as a pale yellow solid (482 mg, 79%): LC-MS: 614 [M+1]⁺.

Step 53b.1-(4-Aminobutyl)-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0303-76)

A mixture of compound 0302-76 (470 mg, 0.77 mmol) and N₂H₄—H₂O (767 mg,15.34 mmol) in CH₂Cl₂ (10.0 mL) and ethanol (1.0 mL) was heated to 50°C. and stirred for 1.5 h. The solvent was removed under reduced pressureand H₂O (25 mL) was added. The mixture was extracted with CH₂Cl₂ (30mL×3). The combined organic layer was washed with H₂O (12 mL×2), driedover Na₂SO₄, filtered and evaporated to give the title compound 0303-76as a pale yellow solid (240 mg, 65%): LC-MS: 483.7 (M+W).

Step 53c.N-(4-(4-Amino-2-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)butyl)acetamide(Compound 76)

A suspension of 0303-76 (240 mg, 0.5 mmol) in acetic acid (1.6 mL) wascooled to 0° C. To this cold solution was added acetic anhydride (204mg, 2.0 mmol). The reaction mixture was allowed to warm to roomtemperature and stirred overnight. The reaction mixture was diluted withCH₂Cl₂ (10 mL) and the solvent was removed under reduced pressure. Theresulting residue was purified by pre-HPLC to give the title compound 76as a white solid (70 mg, 27%): m.p. 198˜201° C., LC-MS: 526.0 (M+H⁺). ¹HNMR (300 MHz, DMSO-d₆) δ 1.33 (m, 2H), 1.69 (m, 2H), 2.97 (m, 2H), 4.16(t, 2H, J=7.2 Hz), 6.05 (s, 2H), 6.36 (s, 2H), 6.66 (s, 1H), 6.80 (d,1H, J=5.7 Hz), 7.48 (s, 1H), 7.70 (d, 1H, J=5.7 Hz), 7.78 (t, 1H, J=4.5Hz).

Example 54 Preparation of2-(6-chlorobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 77) Step 54a.2-(2-(4-Amino-2-(6-chlorobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethyl)isoindoline-1,3-dione(Compound 0302-77)

A mixture of 0206 (2.5 g, 7.8 mmol),2-(2-bromoethyl)isoindoline-1,3-dione (0301) (3.0 mg, 11.7 mmol) andCs₂CO₃ (4.3 g, 2.1 mmol) in anhydrous DMF (28 mL) was stirred at 85° C.for 4 h. The reaction mixture was cooled to room temperature andfiltered. The filtrate was concentrated under high vacuum to give acrude product as an orange solid which was purified by columnchromatography on silica gel (CH₂Cl₂/MeOH=100/1) to provide compound0302-77 (1.5 g, 39%) as a pale yellow solid: LC-MS: 494 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 3.93 (t, 2H, J=5.2 Hz), 4.52 (t, 2H, J=5.2 Hz),6.05 (s, 2H), 6.60 (m, 3H), 6.83 (d, 1H, J=6.0 Hz), 6.99 (s, 1H), 7.66(d, 1H, J=6.0 Hz), 7.76 (m, 4H).

Step 54b.1-(2-Aminoethyl)-2-(6-chlorobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(0303-77)

A mixture of 0302-77 (1.5 g, 3 mmol) and N₂H₄—H₂O (1.8 g, 85%, 85.5mmol) in CH₂Cl₂ (50 mL) and EtOH (5 mL) was heated to 50° C. and stirredfor 3 h. The solid was removed by filtration and the filtrate was washedwith brine (100 mL×2). The organic layer was dried over Na₂SO₄, filteredand concentrated to give the title product 0303-77 (850 mg, 77%) as anorange solid: LC-MS: 364 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.98 (s,2H) 2.80 (m, 2H), 4.18 (t, 2H, J=6.4 Hz), 6.09 (s, 2H), 6.31 (s, 2H),6.76 (s, 1H), 6.84 (d, 1H, J=5.6 Hz), 7.24 (s, 1H), 7.69 (d, 1H, J=5.6Hz).

Step 54c.2-(6-Chlorobenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 77)

To a solution of 0303-77 (850 mg, 2.34 mmol) in methanol (33 mL) wasadded pivalaldehyde (242 mg, 2.8 mmol). After stirred for 30 min at roomtemperature, NaBH₃CN (588 g, 9.36 mmol) was added slowly, and themixture was stirred for another 30 min. The mixture was diluted withwater (500 mL) and extracted with dichloromethane (100 mL×2). Theextract was concentrated and purified by column chromatography on silicagel (CH₂Cl₂/MeOH=50/1) and crystallization (CH₂Cl₂/Et₂O=¼) to give thetitle compound 77 (195 mg, 19%) as a light yellow solid: m.p. 160˜161°C. LCMS: 434 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 0.76 (s, 9H), 1.60 (s, 1H), 2.17(s, 2H), 2.76 (m, 2H), 4.24 (t, 2H, J=6.0 Hz), 6.07 (s, 2H), 6.32 (s,2H), 6.68 (s, 1H), 6.83 (d, 1H, J=6.0 Hz), 7.24 (s, 1H), 7.70 (d, 1H,J=5.6 Hz).

Example 55 Preparation of2-(6-methylbenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 78) Step 55a. 5-Iodo-6-methylbenzo[d][1,3]dioxole (Compound0107-78)

NIS (6.6 g, 29.4 mmol) was added into a solution of compound3,4-(methylenedioxy)toluene (5 g, 36.7 mmol) in MeCN (250 ml). To thismixture was added TFA (8.35 g, 73.4 mmol). The mixture was stirredovernight at room temperature. The solution was concentrated to leave aresidue which was purified by column chromatography on silica to providecompound 0107-78 (12.3 g, 63%) as a red liquid. 1H NMR (DMSO-d⁶): δ 2.26(s, 3H), 5.99 (s, 2H), 6.94 (s, 1H), 7.30 (s, 1H).

Step 55b.1-(4-Methoxybenzyl)-2-(6-methylbenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0205-78)

A mixture of compound 0204 (2.86 g, 10 mmol), compound 0107-78 (3.14 g,12 mmol), NaOt-Bu (960 mg, 10 mmol), neocuproine hydrate (208 mg, 1mmol) and CuI (190 mg, 1 mmol) in dry DMF (60 ml) was stirred at 110° C.overnight. The mixture was concentrated and purified by columnchromatography on silica gel (CH₂Cl₂/MeOH=100/1) to provide compound0205-78 (2.0 g, 48%) as an orange solid. LCMS: 421 [M+1]⁺; 1H NMR(DMSO-d⁶): δ 2.26 (s, 3H), 3.69 (s, 3H), 5.38 (s, 2H), 5.98 (s, 2H),6.80 (m, 7H), 7.05 (d, J=8 Hz, 2H), 7.66 (s, 1H).

Step 55c.2-(6-Methylbenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-78)

A mixture of compound 0205-78 (2.0 g, 4.76 mmol) and CF₃COOH (20 ml) wasstirred at 85° C. for 4 h. The mixture was concentrated and diluted withwater (50 ml). The resulting solid was collected to provide the titlecompound 0206-78 (1.4 g, 78%) as a brown solid: LCMS: 301 [M+1]⁺; 1H NMR(DMSO-d⁶): δ 2.28 (s, 3H), 6.06 (s, 2H), 6.87 (s, 2H), 7.02 (s, 1H),7.15 (s, 1H), 7.58 (s, 1H), 7.93 (s, 1H), 12.98 (s, 1H).

Step 55d.2-(2-(4-Amino-2-(6-methylbenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethyl)isoindoline-1,3-dione(Compound 0302-78)

A mixture of compound 0206-78 (1.4 g, 4.67 mmol),2-(2-bromoethyl)isoindoline-1,3-dione (1.78 g, 7.00 mmol), and Cs₂CO₃(2.58 g, 7.93 mmol) in DMF (40 ml) was stirred for 4 h at 80° C. Thereaction was filtered and the filtrate was concentrated. The product waspurified by column chromatography (dichloromethane/methanol=20/1) toprovide the title compound 0302-78 (760 mg, 34%) as a brown solid: LCMS:474 [M+1]⁺; 1H NMR (DMSO-d⁶): δ 2.12 (s, 3H), 3.90 (t, J=5.4 Hz, 2H),4.44 (t, J=5.4 Hz, 2H), 5.96 (s, 2H), 6.59 (s, 2H), 6.78 (t, 3H), 7.61(d, J=5.6 Hz, 1H), 7.78 (m, 4H).

Step 55e.1-(2-Aminoethyl)-2-(6-methylbenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0303-78)

To a mixture of H₂NNH₂H₂O (800 mg, 16.1 mmol) indichloromethane/methanol (30 ml, 10:1) was added compound 0302-78 (760mg, 1.61 mmol). The mixture was stirred for 4 h at room temperature andthen filtered. The filtrate was washed with brine and the organic phasewas concentrated to provide the title compound 0303-78 (500 mg, 90%) asan orange solid: LCMS: 344 [M+1]⁺; 1H NMR (DMSO-d⁶): δ 1.93 (br, 2H),2.32 (s, 3H), 2.75 (t, J=6.4 Hz, 2H), 4.11 (t, J=6.8 Hz, 2H), 5.99 (s,2H), 6.16 (s, 2H), 6.79 (m, 2H), 6.93 (s, 1H), 7.64 (d, J=5.6 Hz, 1H).

Step 55f.2-(6-Methylbenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 78)

NaBH₃CN (366 mg, 5.82 mmol) was added to a solution of compound 0303-78(500 mg, 1.46 mmol) and pivalaldehyde (151 mg, 1.75 mmol) in methanol(20 ml). The mixture was stirred for 0.5 h at room temperature.Dichloromethane (40 ml) was added into the above mixture and washed withbrine for 3 times. The organic phase was dried over MgSO₄ andconcentrated to give crude product which was purified by columnchromatography (dichloromethane/methanol=20/1) and followed byrecrystallization with dichloromethane and ether to provide the titlecompound 78 (30 mg, 5%) as a white solid: mp 155-156° C.; LCMS: 344[M+1]⁺; 1H NMR (DMSO-d⁶) δ 0.76 (s, 9H), 2.17 (s, 2H), 2.33 (s, 3H),2.70 (t, J=6.2 Hz, 2H), 4.18 (t, J=6.2 Hz, 2H), 5.98 (s, 2H), 6.20 (s,2H), 6.78 (t, 2H), 6.93 (s, 1H), 7.65 (d, J=5.6 Hz, 1H).

Example 56 Preparation of2-(6-(methylthio)benzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 87) Step 56a. 5-(Methylthio)benzo[d][1,3]dioxole (Compound0106-87)

To a suspension of magnesium turnings (2.25 g, 93.7 mmol) in anhydrousTHF (50 mL) was added dropwise 5-bromo-1,3-benzodioxl (15.03 g, 75.1mmol) over 1.5 h under an atmosphere of nitrogen. After being heatedunder reflux for 1 h. the mixture was cooled to −45° C. and poweredsulfur (2.43 g, 75 mmol) was added to it. The mixture was stirred at−45° C. for 1.5 h and then at room temperature for 1.5h, at which timewater (4.1 mL) and 6M HCl (22.5 mL) were added to it. Then withoutpurification adjust the reaction PH to 7.5, and then CH₃I (10.8 mL) wasadded followed by TEBA. The mixture was extracted with CH₂Cl₂, and thecrude product was purified by column chromatography on silica gel(PE=100%) to provide the title product 0106-87 (7.034 g, 55.8%) as awhite soil: ¹H NMR (400 MHz, DMSO-d₆) δ 2.41 (s, 3H), 5.99 (s, 2H), 6.75(q, 1H, J=2 Hz, 8 Hz), 6.86 (d, 1H, J=8 Hz), 6.92 (d, 1H, J=1.6 Hz).

Step 56b. 5-iodo-6-(methylthio)benzo[d][1,3]dioxole (Compound 0107-87)

A mixture of 0106-87 (9.034 g, 53.8 mmol), HNO₃ (5.4 ml), (CH₃CO)₂O (108ml) was stirred at −10° C. for 2h. The reaction was then poured onto theice water for 0.5 h. The resulting yellow solid was collected to provide5-(methothio)-6-nitrobenzo[d][1,3]dioxole (6.2 g, 54.3%): LCMS: 214[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 2.49 (s, 3H), 6.25 (s, 2H), 7.12 (s,1H), 7.79 (s, 1H).

A mixture of 5-(methothio)-6-nitrobenzo[d][1,3]dioxole (6.2 g, 29.2mmol), Fe (16.36 g, 29.2 mmol), HCl (11.68 ml) in EtOH (73 ml) and H₂O(180 ml) was stirred at 110° C. for 2h. The reaction mixture wasadjusted the PH to 11 and filtered. The filtrate was concentrated andpurified by column chromatography on silica gel (petroleum ether/ethylacetate=10/1) to get 6-(methylthio)benzo[d][1,3]dioxol-5-amine as a darkliquid (3.6 g, 67.3%): LCMS: 184 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 2.3(s, 3H), 5.05 (s, 2H), 5.86 (s, 2H) 6.39 (s, 1H), 6.83 (s, 1H).

The above prepared 6-(methylthio)benzo[d][1,3]dioxol-5-amine (3.6 g) wasadded into the mixture of H₂SO₄ (8.07 ml), CH₃CN (150 ml) and AcOH (225ml) in water (150 ml) at 0° C. The mixture was stirred until becoming aclear solution. To this solution was added NaNO₂ (1.495 g) at 0° C. Themixture was warmed to room temperature and allowed to stir at rt for 30min. The solution was slowly dropped into a solution of KI (9.811 g) inwater (150 ml) at 50° C., cooled to room temperature to get a blacksolid which was purified by column chromatography on silica gel(petroleum ether) to obtain the title compound 0107-87 (3.4 g, 58.8%).¹H NMR (400 MHz, DMSO-d₆) δ 2.3 (s, 3H), 6.05 (s, 2H), 6.94 (s, 1H),7.38 (s, 1H).

Step 56c.1-(4-Methoxybenzyl)-2-(6-(methylthio)benzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0205-87)

The title compound 0205-87 was prepared (1.1 g, 65.3%) as a brown solidfrom compound 0204 (943 mg, 3.4 mmol), 0107-87 (2 g, 6.8 mmol),neocuproine hydrate (71 mg, 3.4 mmol), CuI (64.7 mg, 3.4 mmol) andNaOt-Bu (490 mg, 5.1 mmol) in anhydrous DMF (50 mL) using a proceduresimilar to that described for compound 0205-78 (Example 55): LCMS: 453[M+1]⁺; ¹H NMR (DMSO-d⁶) δ 3.68 (s, 3H), 5.37 (s, 2H), 6.00 (s, 2H),6.45 (s, 2H), 6.64 (s, 1H), 6.81 (d, 2H, J=9.2 Hz), 6.94 (s, 1H), 7.04(d, 2H, J=9.2 Hz), 7.65 (s, 1H).

Step 56d.2-(6-(Methylthio)benzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-87)

The title compound 0206-87 was prepared (879 mg, 100%) as a yellow solidfrom compound 0205-87 (1.1 g, 2.45 mmol) and TFA (15 mL) using aprocedure similar to that described for compound 0206-78 (Example 55):LCMS: 333 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 2.40 (s, 3H), 6.09 (s, 2H), 6.74(d, 1H, J=6.8 Hz,), 7.03 (s, 1H), 7.11 (s, 3H), 7.53 (d, 1H, J=5.6 Hz).

Step 56e. tert-Butyl2-(4-amino-2-(6-(methylthio)benzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethylcarbamate(Compound 0305-87)

A mixture of 0206-87 (879 mg, 2.65 mmol), tert-butyl2-bromoethylcarbamate (891 mg, 3.975 mmol) and Cs₂CO₃ (1.464 g, 4.5mmol) in anhydrous DMF (25 ml) was heated to 80° C. and stirred for 2 h.The reaction mixture was cooled to room temperature and filtered. Thefiltrate was concentrated to remove DMF under high vacuum to give acrude product as an orange solid which was purified by columnchromatography on silica gel (CH₂Cl₂/MeOH=50/1) to provide the titlecompound 0305-87 (372 mg, 29.5%) as a yellow solid: LC-MS: 476 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 1.26 (s, 9H), δ 2.43 (s, 3H), 3.22 (t, 2H,J=6.6 Hz) 4.18 (t, 2H, J=6.6 Hz), 6.03 (s, 2H), 6.83 (t, 2H, J=5 Hz),6.96 (s, 1H), 7.08 (s, 1H), 7.67 (d, 1H, J=5 Hz).

Step 56f.1-(2-Aminoethyl)-2-(6-(methylthio)benzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0303-87)

A mixture of TFA (1.8 ml) and compound 0305-87 (372 mg, 995 mmol) inCH₂Cl₂ (10 mL) was stirred at rt for 2 h. Saturated NaHCO₃ solution wasadded and was then extracted with dichloromethane. The organic phase wasisolated and evaporated to obtain the title compound 0303-87 as a solid(260 mg, 88.7%): LCMS: 376 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 2.45 (s,3H), 2.793 (t, 3H, J=6.6 Hz) 4.18 (t, 2H, J=6.6 Hz), 6.04 (s, 2H), 6.24(s, 2H), 6.77 (s, 1H), 6.82 (d, 1H, J=6.0 Hz), 7.02 (s, 1H), 7.67 (d,1H, J=6 Hz).

Step 56g.2-(6-(Methylthio)benzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 87)

To a solution of compound 0303-87 (245 mg, 65.3 mmol) in methanol (15mL) was added pivalaldehyde (84.41 g, 980 mmol). After stirred for 30min at room temperature, NaBH₃CN (164.14 mg, 2.612 mmol) was addedslowly, and the mixture was stirred for another 30 min. The mixture wasdiluted with water (500 mL) and extracted with dichloromethane (500mL×2). The extract was concentrated and purified by columnchromatography on silica gel (CH₂Cl₂/MeOH=50/1) and crystallization(CH₂Cl₂/Et₂O=¼) to give the title compound 87 (52 mg, 17.9%) as a whitesolid: m.p. 170˜170° C. LCMS: 446 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 0.75 (s,9H), 1.56 (s, 1H), 2.16 (s, 2H), 2.43 (s, 2H), 2.72 (s, 2H), 4.22 (t,2H), 6.02 (s, 2H), 6.25 (s, 2H), 6.68 (s, 1H), 6.79 (d, 1H, J=5.2 Hz),7.01 (s, 1H), 7.66 (d, 1H, J=5.2 Hz).

Example 57 Preparation of2-(6-methoxybenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 79) Step 57a. 5-Methoxybenzo[d][1,3]dioxole (Compound 0106-79)

NaOH (1.2 g, 30 mmol) was added into a solution of sesamol (2.76 g, 20mmol) in methanol (15 ml) at 0° C. The mixture was stirred for 1 h at 0°C. and then MeI (3.41 g, 24 mmol) was added into the above solutiondropwise. The reaction mixture was stirred for 3 h at room temperature.The solution was concentrated and purified by column chromatography(petroleum ether) to give compound 0106-79 (2.5 g, 82%) as a colorlessliquid: ¹H NMR (DMSO-d⁶) δ 3.67 (s, 3H), 5.94 (s, 2H), 6.33 (dd, 1H),6.60 (d, J=2.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H).

Step 57b. 5-Iodo-6-methoxybenzo[d][1,3]dioxole (Compound 0107-79)

To a mixture of NIS (3.38 g, 15 mmol) and compound 0106-79 (2.28 g, 15mmol) in MeCN (100 ml) was added TFA (3.42 g, 30 mmol). The reactionmixture was stirred overnight at room temperature. The reaction wasconcentrated and purified by column chromatography on silica (petroleumether) to provide the title compound 0107-79 (3.3 g, 79%) as a whitesolid: ¹H NMR (DMSO-d⁶) δ 3.74 (s, 3H), 5.60 (s, 2H), 6.85 (s, 1H), 7.27(s, 1H).

Step 57c.2-(6-Methoxybenzo[d][1,3]dioxol-5-ylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0205-79)

The title compound 0205-79 was prepared (800 mg, 26%) as a brown solidfrom compound 0204 (2.0 g, 7 mmol), compound 0107-79 (2.33 g, 8.4 mmol),NaOt-Bu (672 mg, 7 mmol), neocuproine hydrate (146 mg, 0.7 mmol) and CuI(133 mg, 0.7 mmol) in dry DMF (40 ml) using a procedure similar to thatdescribed for compound 0205-78 (Example 55): LCMS: 437 [M+1]⁺; ¹H NMR(DMSO-d⁶) δ 3.70 (s, 6H), 5.43 (s, 2H), 5.99 (s, 2H), 6.79 (s, 1H), 6.84(d, 3H), 7.01 (s, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.43 (s, 2H), 7.69 (s,1H).

Step 57d.2-(6-Methoxybenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-79)

The title compound 0206-79 was prepared (570 mg, 98%) as a brown solidfrom compound 0205-79 (0.8 g, 1.83 mmol) and CF₃COOH (10 ml) using aprocedure similar to that described for compound 0206-78 (Example 55):LCMS: 317 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 3.74 (s, 3H), 6.07 (s, 2H), 6.82(d, 2H), 7.01 (s, 1H), 7.10 (s, 1H), 7.60 (m, 2H), 12.71 (br, 1H).

Step 57e. tert-Butyl2-(4-amino-2-(6-methoxybenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethylcarbamate(Compound 0305-79)

The title compound 0305-79 was prepared (200 mg, 25%) as a brown solidfrom compound 0206-79 (570 mg, 1.8 mmol), tert-butyl2-bromoethylcarbamate (605 mg, 2.7 mmol) and Cs₂CO₃ (997 mg, 3.1 mmol)in DMF (15 ml) using a procedure similar to that described for compound0305-87 (Example 56): LCMS: 460 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 1.29 (s, 9H),3.20 (m, 2H), 3.73 (s, 3H), 4.21 (t, J=5.6 Hz, 2H), 5.98 (s, 2H), 6.33(s, 2H), 6.72 (d, J=6.0 Hz, 2H), 6.89 (s, 1H), 7.65 (d, J=6.0 Hz, 1H).

Step 57f.1-(2-Aminoethyl)-2-(6-methoxybenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0303-79)

A solution of compound 0305-79 (1.0 g, 2.18 mmol) and TFA (4 mL) inCH₂Cl₂ (50 mL) was stirred at room temperature for 2 h. The mixture wasadjusted to pH 8-9 with saturated Na₂CO₃ aqueous solution and extractedby CH₂Cl₂. The organic layer was separated and dried over Na₂SO₄,concentrated to obtain the title compound 0303-79 (734 mg, 93%) whichwas used directly to the next step without further purification: LCMS:360 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 2.78 (t, J=6.4 Hz, 2H), 3.71 (m, 2H),3.75 (s, 3H), 5.99 (s, 2H), 6.23 (s, 2H), 6.70 (s, 1H), 6.80 (d, J=6.0Hz, 1H,), 6.91 (s, 1H), 7.66 (d, J=6.0 Hz, 1H).

Step 57g.2-(6-methoxybenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 79)

To a solution of compound 0303-79 (734 mg, 2.04 mmol) in methanol (40mL) was added pivalaldehyde (352 mg, 4.08 mmol). After stirred for 30min at room temperature, NaBH₃CN (423 mg, 6.7 mmol) was added slowly,and the mixture was stirred for another 30 min. The mixture was dilutedwith water (100 mL) and extracted with dichloromethane (100 mL×2). Theextract was concentrated and purified by column chromatography on silicagel (CH₂Cl₂/MeOH=50/1) and crystallization (CH₂Cl₂/Et₂O=¼) to give thetitle compound 79 (151 mg, 17%) as a yellow solid: m.p. 164˜167° C.LCMS: 430 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 0.78 (s, 9H), 2.19 (s, 2H), 2.74(t, J=6.0 Hz, 2H), 3.76 (s, 3H), 4.25 (t, J=6.0 Hz, 2H), 5.99 (s, 2H),6.25 (s, 2H), 6.66 (s, 1H), 6.81 (d, J=6.0 Hz, 1H), 6.92 (s, 1H), 7.68(d, J=6.0 Hz, 1H).

Example 58 Preparation of2-(6-tert-butylbenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 86) Step 58a. 5-tert-Butylbenzo[d][1,3]dioxole (Compound0106-86)

Aqueous NaOH (8 g, 100 mmol, 50%) was added slowly into a solution of4-tert-butylcatechol (8.3 g, 50 mmol) in DMSO (100 ml) at 90° C. Thesolution was stirred for 1 h at 90° C. and then CH₂₁₂ (10 ml) was addeddropwise into the above solution. The mixture was stirred for 2 h at 90°C. and was distilled under reduced pressure to give the title compound0106-86 (4 g, 45%) as a colorless liquid: ¹H NMR (400M): (DMSO-d⁶) δ1.23 (s, 9H), 5.95 (s, 2H), 6.80 (s, 2H), 6.98 (s, 1H).

Step 58b. 5-tert-Butyl-6-iodobenzo[d][1,3]dioxole (Compound 0107-86)

HNO₃ (4.5 ml) was added into a solution of compound 0106-86 (8 g, 45mmol) in Ac₂O (90 ml) at −10° C. The mixture was stirred for 2 h at −10°C. The PH of the mixture was adjusted to 7-8 with 10% NaOH.Dichloromethane (200 ml) and water (100 ml) was added into the abovemixture and was extracted with dichloromethane for 3 times. The organicphase was dried over MgSO₄, filtered and concentrated to give5-tert-Butyl-6-nitrobenzo[d][1,3]dioxole (9.5 g, 95%) as a yellowliquid. 1H NMR (400M): (DMSO-d⁶) δ 1.29 (s, 9H), 6.13 (s, 2H), 7.16 (s,1H), 7.24 (s, 1H).

The above prepared 5-tert-Butyl-6-nitrobenzo[d][1,3]dioxole (1.1 g, 5mmol), Fe (5.5 g, 100 mmol) and HCl (2 ml) was added into ethanol (6 ml)and water (18 ml). The mixture was stirred for 2 h at refluxedtemperature. The PH was adjusted to 7-8 and the mixture was filtered andwashed with methanol. The filtrate was concentrated and purified bycolumn chromatography (petroleum ether/ethyl acetate 1%-5%) to give6-tert-butylbenzo[d][1,3]dioxol-5-amine (240 mg, 25%) as a red solid.LCMS: 194 [M+1]⁺; 1H NMR (400M): (DMSO-d⁶) δ 1.28 (s, 9H), 4.46 (s, 2H),5.77 (s, 2H), 6.32 (s, 1H), 6.63 (s, 1H).

6-tert-butylbenzo[d][1,3]dioxol-5-amine (1.55 g, 8.03 mmol) was added toa solution of H₂SO₄ (5.51 g, 56.22 mmol) in MeCN (60 ml) and water (60ml) at 0° C. NaNO₂ (0.61 g, 8.83 mmol) was then added to the abovemixture. The reaction mixture was stirred for 1 h at 0° C. and then asolution of KI (4 g, 24.1 mmol) in water (60 ml) was added dropwise. Thereaction mixture was stirred overnight at room temperature. Theresulting solid was collected and purified by column chromatography(petroleum ether) to give the title compound 0107-86 (2.2 g, 90%) as awhite solid. 1H NMR (400M): (DMSO-d⁶) δ 1.44 (s, 9H), 6.00 (s, 2H), 7.01(s, 1H), 7.46 (s, 1H).

Step 58c.2-(6-tert-Butylbenzo[d][1,3]dioxol-5-ylthio)-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0205-86)

The title compound 0205-86 was prepared (1.8 g, 56%) as a brown solidfrom compound 0204 (2.0 g, 7 mmol), compound 0107-86 (2.13 g, 7 mmol),NaOt-Bu (672 mg, 7 mmol), neocuproine hydrate (146 mg, 0.7 mmol), andCuI (133 mg, 0.7 mmol) in dry DMF (40 ml) using a procedure similar tothat described for compound 0205-78 (Example 55): LCMS: 463 [M+1]⁺; ¹HNMR (DMSO-d⁶) δ 1.41 (s, 9H), 3.71 (s, 3H), 5.43 (s, 2H), 6.01 (s, 2H),6.66 (s, 1H), 6.88 (d, J=8.8 Hz, 2H), 7.02 (s, 1H), 7.13 (m, 3H), 7.55(s, 2H), 7.70 (s, 1H).

Step 58d.2-(6-tert-Butylbenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0206-86)

The title compound 0206-86 was prepared (1.3 g, 98%) as a brown solidfrom compound 0205-86 (1.8 g, 3.9 mmol) and CF₃COOH (20 ml) using aprocedure similar to that described for compound 0206-78 (Example 55):LCMS: 343 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 1.43 (s, 9H), 6.08 (s, 2H), 6.91(d, J=5.6 Hz, 1H), 7.10 (d, 1H), 7.59 (d, J=6.8 Hz, 1H), 8.40 (s, 2H),13.11 (s, 1H).

Step 58e. tert-Butyl2-(4-amino-2-(6-tert-butylbenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-1-yl)ethylcarbamate(Compound 0305-86)

The title compound 0305-86 was prepared (440 mg, 24%) as a brown solidfrom compound 0206-86 (1.3 g, 3.8 mmol), tert-butyl2-bromoethylcarbamate (1.3 g, 5.7 mmol), and Cs₂CO₃ (2.1 g, 6.5 mmol) inDMF (40 ml) using a procedure similar to that described for compound0305-87 (Example 56): LCMS: 486 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 1.27 (s, 9H),1.50 (s, 9H), 3.25 (d, 2H), 4.20 (s, 2H), 5.98 (s, 2H), 6.32 (s, 2H),6.67 (s, 1H), 6.75 (d, J=4.8 Hz, 1H), 7.01 (m, 2H), 7.67 (d, J=5.2 Hz,1H).

Step 58f.1-(2-Aminoethyl)-2-(6-tert-butylbenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 0303-86)

The title compound 0303-86 was prepared (349 mg, 95%) from compound0305-86 (445 g, 0.92 mmol) and TFA (4 mL) in CH₂Cl₂ (50 mL) using aprocedure similar to that described for compound 0303-79 (Example 57):LCMS: 386 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 1.50 (s, 9H), 2.78 (t, J=6.4 Hz,2H), 3.17 (s, 2H), 4.10 (t, J=6.4H, 3H), 5.98 (s, 2H), 6.20 (s, 2H),6.57 (s, 1H), 6.84 (d, J=6.0 Hz, 1H), 7.02 (s, 1H), 7.69 (d, J=6.0 Hz,1H).

Step 58g.2-(6-tert-Butylbenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 86)

The title compound 86 was prepared (190 mg, 46%) as yellow solid fromcompound 0303-86 (349 mg, 0.9 mmol), pivalaldehyde (156 mg, 1.8 mmol)and NaBH₃CN (226 mg, 3.6 mmol) using a procedure similar to thatdescribed for compound 79 (Example 57): m.p. 142˜148° C. LCMS: 456[M+1]⁺; ¹H NMR (DMSO-d⁶) δ 0.77 (s, 9H), 1.52 (s, 9H), 2.18 (s, 2H),2.76 (t, J=8.4 Hz, 2H), 4.22 (t, J=8.4 Hz, 2H), 5.97 (s, 2H), 6.34 (s,2H), 6.51 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.02 (s, 1H), 7.70 (d, J=8.0Hz, 1H).

Example 59 Preparation of1-(2-(neopentylamino)ethyl)-2-(6-vinylbenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 84) Step 59a. 2,4-Dihydroxy-3-nitropyridine (Compound 0108)

Fuming HNO₃ (90 mL) was added to a stirring solution of2,4-dihydroxypyridine (0601) (100 g, 0.9 mol) in con. H₂SO₄ (300 mL) at0° C. After 45 min, the solution was poured into crushed ice and themixture was chilled in a freezer. The resulting precipitate wasfiltered, washed with cold water, and dried to give the title compound0108 (135 g, 96%) as a light yellow solid: LCMS: 157 [M+1]⁺; ¹H NMR(DMSO-d⁶) δ 6.05 (d, 1H, J=7.2 Hz), 7.47 (d, 1H, J=7.2 Hz), 11.91 (s,1H), 12.47 (s, 1H).

Step 59b. 2,4-Dichloro-3-nitropyridine (Compound 0109)

Compound 0108 (10 g, 64 mmol) was dissolved in POCl₃ (70 mL) and heatedovernight at 85° C. The excess POCl₃ was evaporated at atmospherepressure. The residuum was neutralized (pH7) with saturated NaHCO₃. Theprecipitate was filtered and dried to give the title compound 0109 (9.95g, 80.5%) as a yellow solid: ¹H NMR (CDCl₃) δ 7.47 (d, J=5.7 Hz, 1H),8.44 (d, J=5.1 Hz, 1H).

Step 59c. tert-Butyl 2-(2-chloro-3-nitropyridin-4-ylamino)ethylcarbamate(Compound 0602-84)

A mixture of compound 0109 (55 g, 0.285 mol), tert-butylN-(2-aminoethyl)carbamate (59.3 g, 0.37 mol) and Et₃N (43.2 g, 0.427mol) in DMF (450 mL) was heated to 65° C. and stirred for 2.5 h. The DMFwas removed under reduced pressure and the residue was poured intobrine, extracted with EtOAc, dried and concentrated. The residue wasthen recrystallized with EtOH-water to provide the title compound0602-84 (65 g, 72%) as a yellow solid: LCMS: 317 [M+1]⁺; ¹H NMR(DMSO-d⁶) δ 1.36 (s, 9H), 3.10 (q, 2H, J₁=8.0 Hz, J₂=16 Hz), 3.30 (q,2H, J₁=8.0 Hz, J₂=16 Hz), 6.98 (d, 2H, J=8 Hz), 7.38 (t, 1H, J=7.2 Hz),8.04 (d, 1H, J=8.0 Hz).

Step 59d. tert-Butyl 2-(3-amino-2-chloropyridin-4-ylamino)ethylcarbamate(Compound 0603-84)

A mixture of compound 0602-84 (70 g, 0.221 mol), iron dust (62 g, 1.105mol) and FeSO₄ 7H₂O (18.5 g, 66 mmol) in saturated NH₄Cl aqueoussolution (750 mL) and MeOH (1400 mL) was heated to 80° C. for 3 h. Thereaction was then filtered and washed with MeOH. The filtrate wasconcentrated and the residue was dissolved in dichloromethane. Thedichloromethane solution was washed with water and concentrated to givethe title compound 0603-84 (55 g, 87%) as a red solid. LCMS: 287 [M+1]⁺;¹H NMR (DMSO-d⁶) δ 1.37 (s, 9H), 3.13 (m, 4H), 4.69 (s, 2H), 5.76 (d,1H, J=5.2 Hz), 6.45 (d, 1H, J=5.6 Hz), 6.92 (d, 1H, J=5.2 Hz), 7.41 (d,1H, J=5.2 Hz).

Step 59e. tert-Butyl2-(4-chloro-2-thioxo-2,3-dihydroimidazo[4,5-c]pyridin-1-yl)ethylcarbamate(Compound 604-84)

A mixture of compound 0603-84 (55 g, 0.192 mol), KOH (54 g, 0.959 mol),CS₂ (73 g, 0.959 mol) in EtOH (500 mL) and H₂O (50 mL) was stirred for12 h at 85° C. Then the mixture was cooled to room temperature anddiluted with water. The mixture was adjusted to pH7 with AcOH, filteredto give the title compound 604-84 (54.5 g, 87%) as a yellow solid: LCMS:329 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 1.20 (s, 9H), 3.33 (s, 2H), 4.24 (t, 2H,J=4.8 Hz), 6.89 (t, 1H, J=5.2 Hz), 7.33 (d, 1H, J=5.2 Hz), 8.14 (d, 1H,J=5.2 Hz), 13.59 (s, 1H).

Step 59f.1-(2-Aminoethyl)-4-chloro-1H-imidazo[4,5-c]pyridine-2(3H)-thione salt(Compound 0605-84)

A mixture of compound 0604-84 (63.8 g, 0.194 mol) and TFA (150 mL, 1.94mol) in dichloromethane (750 mL) was stirred for 2 h at 25° C. Thesolvent was removed and dried to give the title compound 0605-84 (163 g)as a yellow solid which was used directly in next step without furtherpurification: LCMS: 229 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 3.27 (q, 2H, J₁=5.2Hz, J₂=11.2 Hz), 4.47 (t, 2H, J=6.0 Hz), 7.55 (d, 1H, J=5.2 Hz), 7.92(s, 2H), 8.20 (d, 1H, J=5.2 Hz), 12.22 (s, 2H), 13.78 (s, 1H).

Step 59g.4-Chloro-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridine-2(3H)-thione(Compound 0606-84)

A suspension of compound 0605-84 (163 g, 0.194 mol) in MeOH (1300 mL)was adjusted to pH 8 with NEt₃ (˜100 mL) at ice bath. Then pivalaldehyde(33.4 g, 0.388 mol) was added to the mixture and the mixture was stirredfor 30 min at room temperature. NaBH₃CN (48.76 g, 0.776 mol) was addedto the mixture and the mixture was stirred at room temperatureovernight. The resulting solid was filtered to give the title compound0606-84 (38.6 g, total yield of two steps: 67%) as a yellow solid: LCMS:299 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 0.79 (s, H), 2.36 (s, 2H) 2.95 (t, 2H,J=6.0 Hz), 4.32 (t, 2H, J=6.0 Hz), 7.49 (d, 1H, J=5.6 Hz), 8.07 (d, 1H,J=5.6 Hz).

Step 59h.4-Amino-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridine-2(3H)-thione(Compound 0607-84)

A mixture of compound 0606-84 (11.4 g, 38.2 mmol) and sodium amide (30g, 769 mmol) in 400 mL liquid ammonia was stirred at 25° C. for 24 h inan autoclave. Ammonia was volatilized before opening the autoclave.Water was added carefully until all solids were dissolved. This solutionwas adjust pH 7 with acetic acid and filtered to obtain the titlecompound 0607-84 (9 g, 84%) as a gray solid: LCMS: 280 [M+1]⁺; ¹H NMR(DMSO-d⁶) δ 0.792 (s, 9H), 2.27 (s, 2H), 2.84 (m, 2H), 4.19 (m, 2H),6.06 (s, 2H), 6.77 (m, 1H), 7.71 (m, 1H).

Step 59i. 5-Iodo-6-vinylbenzo[d][1,3]dioxole (Compound 0107-84)

To a solution of 3,4-(methylenedioxy)benzyl alcohol (1.8 g, 12 mmol) andCF₃COOAg (3.434 g, 15.5 mmol) in dry CHCl₃ (55 mL) at −5° C. was addedI₂ (3.9 g, 15.5 mmol) in portion. The resulting yellow mixture wasmaintained at −5° C. for 5 min, then filtered. The filtrate was washedwith 20% Na₂S₂O₃, dried and evaporated. The crude was purified by columnchromatography on silica gel (petroleum ether) to obtain(6-iodobenzo[d][1,3]dioxol-5-yl)methanol (1.8 g, 56%) as a white solid.LCMS: 279[M+1]⁺; ¹H NMR (DMSO-d⁶) δ 4.31 (d, 2H, J=4.2 Hz), 5.40 (t, 1H,J=4.2 Hz), 6.03 (s, 2H), 7.03 (s, 1H), 7.34 (s, 2H).

(6-Iodobenzo[d][1,3]dioxol-5-yl)methanol (2.7 g, 9.7 mmol) in dry CH₂Cl₂was added dropwise to PCC (3.1 g, 14.6 mmol) in dry CH₂Cl₂ at 0° C.under N₂ atmosphere. The mixture was stirred at room temperature for20h. After reaction, the crude product was purified by columnchromatography on silica gel (petroleum ether) to obtain6-iodobenzo[d][1,3]dioxole-5-carbaldehyde (2 g, 77%) as white solid.LCMS: 277[M+1]⁺; ¹H NMR (DMSO-d⁶) δ 6.20 (s, 2H), 7.28 (s, 1H), 7.61 (s,1H), 9.79 (s, 1H).

To a mixture of PPh₃CH₃I (5.5 g, 13.5 mmol) in dry THF was added t-BuOK(1.7 g, 14.8 mmol) at 0° C. The reaction mixture was stirred for 20 min.Above prepared compound 6-iodobenzo[d][1,3]dioxole-5-carbaldehyde in THFwas then added to the reaction mixture dropwise. After reaction, thecrude was purified by column chromatography on silica gel (petroleumether) to obtain the title compound 0107-84 (2.65 g, 78%) as whitesolid. LCMS: 275 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 5.24 (d, 1H, J=10.8 Hz),5.65 (d, 1H, J=17.1 Hz), 6.07 (s, 2H), 6.73 (m, 1H), 7.28 (s, 1H), 7.39(s, 1H).

Step 59j.1-(2-(Neopentylamino)ethyl)-2-(6-vinylbenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 84)

A mixture of 0607-84 (100 mg, 0.36 mmol), 0107-84 (118 mg, 0.43 mmol),neocuproine hydrate (7.5 mg, 0.036 mmol), CuI (6.8 mg, 0.036 mmol) andNaOt-Bu (52 mg, 0.54 mmol) in anhydrous DMF (5 mL) was stirred for 12 hat 110° C. (oil bath) under nitrogen atmosphere. The solvent was pouredinto water, the mixture was then extracted with ethyl acetate. Solventswere removed and the crude was purified by prep-TLC (CH₂Cl₂/MeOH at20/1) to obtain the title compound 84 (32 mg, 21%) as a yellow solid:m.p. 175-178° C. LCMS: 547[M+1]⁺; ¹H NMR (DMSO-d⁶) δ 0.77 (s, 9H), 2.18(s, 2H), 2.72 (t, 2H, J=4.5 Hz), 4.21 (t, 2H, J=4.8 Hz), 5.31 (d, 1H,J=8.4 Hz), 5.77 (d, 1H, J=13.5 Hz), 6.05 (s, 2H), 6.28 (s, 2H), 6.81 (m,2H), 7.22 (m, 1H), 7.32 (s, 1H), 7.67 (d, 1H, J=4.5 Hz).

Example 60 Preparation of6-(4-amino-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-2-ylthio)benzo[d][1,3]dioxole-5-carbonitrile(Compound 89) Step 60a. 6-Iodobenzo[d][1,3]dioxole-5-carbonitrile(Compound 0107-89)

A mixture of 5,6-diiodobenzo[1,3]dioxole (1 g, 2.7 mmol) and CuCN (240mg, 2.7 mmol) in DMF (15 mL) was stirred at 140° C. for 16h. The mixturewas filtered and the filtrate was added water. The resulting brown solidwas filtered and purified by column chromatography on silica gel(petroleum ether/ethyl acetate=10/1) to obtain title compound 107-89(450 mg, 61%) as a white solid: LCMS: 274[M+1]⁺; ¹H NMR (DMSO-d⁶) δ 6.20(s, 2H), 7.48 (s, 1H), 7.60 (s, 1H).

Step 60b.6-(4-Amino-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-2-ylthio)benzo[d][1,3]dioxole-5-carbonitrile(Compound 89)

The title compound 89 was prepared (26 mg, 11.4%) as a yellow solid fromcompound 0607-84 (150 mg, 0.54 mmol), 0107-89 (176 mg, 0.64 mmol),neocuproine hydrate (11.2 mg, 0.054 mmol), CuI (10.2 mg, 0.054 mmol) andNaOt-Bu (77 mg, 0.81 mmol) in anhydrous DMF (5 mL) using a proceduresimilar to that described for compound 84 (Example 59): m.p. 126˜130° C.LCMS: 425 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 0.76 (s, 9H), 2.20 (s, 2H), 2.79(t, 2H, J=4.8 Hz), 4.27 (t, 2H, J=4.5 Hz), 6.18 (s, 2H), 6.31 (s, 2H),6.83 (d, 1H, J=4.5 Hz), 6.99 (s, 1H), 7.53 (s, 1H), 7.68 (s, 1H).

Example 61 Preparation of2-(6-iodo-2,2-dimethylbenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 101) Step 61a. 5,6-Diiodo-2,2-dimethylbenzo[d][1,3]dioxole(Compound 0107-101)

A mixture of catechol (10 g, 91 mmol), 2,2-Dimethoxypropane (8.6 g, 82.6mmol) and p-TsOH (33 mg, 0.17 mmol) in toluene (100 ml) was stirred atreflux for 6 h. After reaction, the mixture was cooled to roomtemperature and NaHCO₃ was added to neutralize the mixture. The solventwas removed and the residue was purified by distillation under reducedpressure at 36° C. to obtain 2,2-dimethylbenzo[d][1,3]dioxole (2.34 g,17%) as a yellow oil. ¹H NMR (CDCl₃-d⁶) δ 1.69 (s, 6H), 6.78 (m, 4H).

A solution of compound 2,2-dimethylbenzo[d][1,3]dioxole (2.34 g, 15.6mmol) in MeCN (80 ml) was added NIS (10.5 g, 46.8 mmol) and followedwith TFA (3.56 g, 31.2 mmol). The solution was stirred overnight at roomtemperature. The solution was concentrated and the residue was purifiedby column chromatography on silica (petroleum ether) to provide thetitle compound 0107-101 (5.6 g, 89%) as a white solid: ¹H NMR (CDCl₃-d⁶)δ 1.58 (s, 6H), 7.15 (s, 2H).

Step 61b.2-(6-Iodo-2,2-dimethylbenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 101)

The title compound 101 was prepared (31 mg, 10%) as a white solid fromcompound 0607-84 (200 mg, 0.72 mmol), 0107-101 (431 mg, 1.07 mmol),neocuproine hydrate (15 mg, 0.072 mmol), CuI (14 mg, 0.072 mmol) andNaOt-Bu (69 mg, 0.72 mmol) in anhydrous DMF (5 mL) using a proceduresimilar to that described for compound 84 (Example 59): m.p.: 214-216°C.; LCMS: 554 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 0.76 (s, 9H), 1.60 (s, 6H),2.16 (s, 2H), 2.73 (t, 2H, J=5.6 Hz), 4.24 (t, 2H, J=5.6 Hz), 6.36 (s,2H), 6.51 (s, 1H), 6.84 (d, 2H, J=5.2 Hz), 7.38 (s, 1H), 7.70 (d, 1H,J=5.2 Hz).

Example 62 Preparation of1-(2-(neopentylamino)ethyl)-2-(6-nitrobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 113) Step 62a. 5-Iodo-6-nitrobenzo[d][1,3]dioxole (Compound0107-113)

1, 3-Benzodioxole (10.0 g, 82 mmol) was added dropwise to a solution ofcon. HNO₃ (65%˜68%, 18 g) in H₂O (39 g) at 60˜65° C. The mixture wasthen heated to 90° C. and stirred for 2 h at this temperature. Themixture was cooled to room temperature and poured into ice/water,filtered to give compound 5-nitrobenzo[d][1,3]dioxole (12.0 g, 87%) as ayellow solid. LCMS: 168 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 6.27 (s, 2H), 7.12(d, 1H, J=12 Hz), 7.76 (d, 1H, 3.2 Hz), 7.91 (dd, 1H, J, =12 Hz, J₂=3.2Hz).

Compound 5-nitrobenzo[d][1,3]dioxole (5.0 g, 30 mmol) was added in oneportion to a solution of fuming HNO₃ and con. HNO₃ (V/V=1/1, 120 mL) at−10 to −5° C. The mixture was stirred for 3 h at this temperature andpoured into ice/water, filtered to get compound5,6-dinitrobenzo[d][1,3]dioxole (7.0 g, quantitive) as a yellow solid.The compound was used directly without purification. ¹H NMR (DMSO-d⁶) δ6.39 (s, 2H), 7.86 (s, 2H).

Compound 5,6-dinitrobenzo[d][1,3]dioxole (6.0 g, 28.3 mmol) was added tostirred glacial acetic acid (120 mL) under N₂ atmosphere. After themixture was heated to boiling, the heat source was removed and ironpowder (4.75 g) added with vigorous stirring. Quick spontaneous boilingoccurred, the mixture turned dark and the exothermic reaction subsided(2-5 min). The mixture was refluxed for 10 min and poured intoice/water. The orange-red product was isolated by filtration, dissolvedin glacial acetic acid, and the solution filtered while hot. Thefiltrate was poured into ice-cold water. The orange-red solid productwas isolated by filtration and dried to provide compound6-nitrobenzo[d][1,3]dioxol-5-amine (4.35 g, 84%). LCMS: 183 [M+1]⁺; ¹HNMR (DMSO-d⁶) δ 6.06 (s, 2H), 6.51 (s, 1H), 7.36 (s, 1H), 7.73 (s, 2H).

A suspension of compound 6-nitrobenzo[d][1,3]dioxol-5-amine (2.65 g,14.6 mmol) in con. HCl (15 mL) and water (5 mL) was heated on a steambath for 5 min and then cooled to 5° C. with stirring. A solution ofsodium nitrite (1.0 g, 14.4 mmol) in water (15 mL) was added until allthe solids dissolved. The solution was stirred for additional 5 min anda solution of potassium iodide (2.4 g, 14.5 mmol) in water was thenadded rapidly with vigorous stirring at 5° C. The mixture was filtratedand the residue was dissolved with dichloromethane, dried and purifiedby column chromatograph (ethyl acetate/petroleum ether=1/10) to providethe title compound 0107-113 (1.6 g, 38%) as a yellow solid. 1H NMR(DMSO-d⁶) δ 6.24 (s, 2H), 7.64 (s, 1H), 7.67 (s, 1H).

Step 62b.1-(2-(Neopentylamino)ethyl)-2-(6-nitrobenzo[d][1,3]dioxol-5-ylthio)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 113)

The title compound 113 was prepared (40 mg, 26%) as a yellow solid fromcompound 0607-84 (100 mg, 0.358 mmol), 0107-113 (137 mg, 0.466 mmol),necocuproine (8 mg, 0.036 mmol), CuI (7 mg, 0.036 mmol), and NaO-t-Bu(52 mg, 0.537 mmol) in anhydrous DMF (5 ml) using a procedure similar tothat described for compound 84 (Example 59): m.p. 111˜114° C. LCMS:445[M+1]⁺, ¹H NMR (DMSO-d⁶) δ 0.72 (s, (H), 1.61 (s, 1H), 2.12 (s, 2H),2.74 (t, 2H, J=5.2 Hz), 4.21 (t, 2H, J=5.2 Hz), 6.16 (s, 1H), 6.18 (s,2H), 6.49 9s, 2H), 6.85 (d, 1H, J=6.4 Hz), 7.73 (d, 1H, J=6.4 hz), 7.85(s, 1H).

Example 63 Preparation of2-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-1-(2(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 111)Step 63a. 6-Iodo-N,N-dimethylbenzo[d][1,3]dioxol-5-amine (Compound0107-111)

To a solution of 3,4-(Methylenedioxy)aniline (8 g, 58.3 mmol) in AcOH(120 ml) was added Ac2O (48 mL). The mixture was stirred for overnight.After reaction, the mixture was poured into saturated NaHCO₃ solution,and then filtered. The filtrate was extracted with ethyl acetate to giveN-(benzo[d][1,3]dioxol-5-yl)acetamide (10 g, 95%). LCMS: 180[M+1]⁺; ¹HNMR (DMSO-d⁶) δ 2.0 (s, 3H), 5.96 (s, 2H), 6.82 (d, 1H, J=8.1 Hz), 6.91(d, 1H, J=2.1 Hz), 7.30 (d, 1H, J=1.8 Hz), 9.84 (s, 1H).

A 1.0 M solution of iodine monochloride in methylene chloride (72.6 mL)was added dropwise to a solution ofN-(benzo[d][1,3]dioxol-5-yl)acetamide (10 g, 55.8 mmol) in methylenechloride (66 mL) and acetic acid (11 mL). The mixture was stirred undernitrogen overnight and then washed with saturated sodium thiosulfate(2×150 mL) and brine (150 mL). The methylene chloride solution was dried(MgSO₄) and evaporated, and the residue was purified by columnchromatography on silica gel (CH₂Cl₂/petroleum at 20/1) to obtainN-(6-iodobenzo[d][1,3]dioxol-5-yl)acetamide (3.7 g, 22%) as a whitesolid. LCMS: 306 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 2.00 (s, 3H), 6.06 (s, 2H),6.95 (s, 1H), 7.37 (s, 1H), 9.34 (s, 1H).

A solution of N-(6-iodobenzo[d][1,3]dioxol-5-yl)acetamide (200 mg, 0.656mmol) and NaOH (1.31 g, 32.8 mmol) in ethanol (26 mL) and water (6 mL)was heated to reflux with stirring for 4 h. The mixture was cooled andthe solvent was removed under vacuum. The residue was partitionedbetween methylene chloride (100 mL) and water (100 mL). The organiclayer was washed with water (2×100 mL), dried (MgSO₄) and evaporatedunder vacuum to give 6-iodobenzo[d][1,3]dioxol-5-amine (170 mg, 98%) asorange solid. LCMS: 264 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ 4.88 (s, 2H), 5.87(s, 2H), 6.47 (s, 1H), 7.07 (s, 1H).

To a solution of 6-iodobenzo[d][1,3]dioxol-5-amine (1 g, 3.8 mmol) andparaformaldehyde (1.14 g, 38 mmol) in methanol (10 mL) was added NaBH₃CN(2.39 g, 38 mmol) slowly with stirring. The mixture was heated to 50° C.for 4 h. Water (100 mL) was added and extracted with methylene chloride(100 mL). The organic layer was washed with brine (100 mL), dried(MgSO₄) and evaporated under vacuum to give crude title compound0107-111 (1.16 g) as a brown oil which was used directly to the nextstep without further purification. LCMS: 292 [M+1]⁺; ¹H NMR (DMSO-d⁶) δ2.56 (s, 6H), 6.02 (s, 2H), 6.96 (s, 1H), 7.32 (s, 1H).

Step 63b.2-(6-(Dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine (Compound 111)

The title compound 111 was prepared (20 mg, 6.6%) as a brown solid fromcompound 0607-84 (190 mg, 0.68 mmol), 0107-111 (200 mg, 0.68 mmol),neocuproine hydrate (14 mg, 0.068 mmol), CuI (12 mg, 0.068 mmol) andNaOt-Bu (66 mg, 0.068 mmol) in anhydrous DMF (6 mL) using a proceduresimilar to that described for compound 84 (Example 59): LCMS: 443[M+1]⁺; ¹H NMR (DMSO-d⁶) δ 0.748 (s, 9H), 2.16 (s, 2H), 2.63 (s, 6H),2.74 (t, 2H, J=6.0 Hz), 4.21 (t, 2H, J=6.0 Hz) 5.94 (s, 2H), 6.16 (s,1H), 6.38 (s, 2H), 6.84 (d, 1H, J=6.0 Hz), 7.01 (s, 1H), 7.70 (d, 1H,J=5.6 Hz).

Example 64 Preparation of2-(6-((dimethylamino)methyl)benzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 115) Step 64a.N-((6-Iodobenzo[d][1,3]dioxol-5-yl)methyl)acetamide compound (Compound0107-115)

To a solution of 3,4-methylenedioxybenzylamine (10 g, 66.2 mmol) inacetic acid (50 mL) was added acetic anhydride (15.27 g, 150 mmol). Themixture was stirred at 20° C. for 30 minutes. Then it was adjusted toPH7 with 10% NaOH. The mixture was filtered to obtain a solid which waswashed water and dried in vacuum to giveN-(benzo[d][1,3]dioxol-5-ylmethyl)acetamide as a white solid (9.24 g,77%). LC-MS: 194 [M+1]⁺; ¹H-NMR (DMSO-d⁶): δ 1.84 (s, 3H), 4.12 (d, 2H,J=6.4 Hz), 5.98 (s, 2H), 6.71 (m, 2H), 6.83 (m, 2H), 8.28 (s, 1H).

N-(benzo[d][1,3]dioxol-5-ylmethyl)acetamide (9.24 g, 47.9 mmol) wasadded to 1.0 M solution of iodine monochloride in methylene chloride (80mL). The mixture was stirred at room temperature for 2 hours, and thenthe mixture was poured into 10% Na₂S₂O₃ and stirred until the red colorfaded. It was then extracted with CH₂Cl₂ and the organic layer waswashed with water and brine, dried and concentrated to get the crudeproduct which was purified by column chromatography (mobile phase:petroleum/methylene chloride=1/19) to giveN-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)acetamide compound as a whitesolid (5.82 g, 38%). LC-MS: 320 [M+1]⁺. ¹H-NMR (DMSO-d⁶): δ 1.89 (s,3H), 4.11 (d, 2H, J=6.0 Hz), 6.04 (s, 2H), 7.07 (s, 1H), 7.37 (s, 1H),8.28 (t, 1H, J=6.0 Hz).

N-((6-Iodobenzo[d][1,3]dioxol-5-yl)methyl)acetamide (2.4 g, 7.5 mmol)was added to methanolic hydrochloric acid solution (4 N) (60 mL). Themixture was stirred at 80° C. overnight. Solvent was removed and theresidue was dissolved in water, adjusted to PH7 with 10% NaHCO₃,filtered to obtain (6-iodobenzo[d][1,3]dioxol-5-yl)methanamine as ayellow solid (1.76 g, 85%). LC-MS: 278 [M+1]⁺. ¹H-NMR (DMSO-d⁶): δ 1.88(s, 2H), 3.57 (s, 2H), 6.02 (s, 2H), 7.13 (s, 1H), 7.33 (s, 1H).

A mixture of (6-iodobenzo[d][1,3]dioxol-5-yl)methanamine (1.76 g, 6.35mmol), NaBH₃CN (4.00 g, 63.5 mmol), and formaldehyde (1.9 g, 63.5 mmol)in methanol (10 mL) was stirred at 50° C. for 2 hours. The solvent wasremoved and the residue was dissolved in CH₂Cl₂, washed with water andbrine, dried and concentrated to give the title compound 0107-115 as ayellow oil (700 mg, 36%). LC-MS: 306 [M+1]⁺. ¹H-NMR (DMSO-d⁶): δ 2.15(s, 6H), 3.29 (s, 2H), 6.02 (s, 2H), 6.95 (s, 1H), 7.33 (s, 1H).

Step 64b.2-(6-((Dimethylamino)methyl)benzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 115)

The title compound 115 was prepared (27 mg, 15%) as a yellow solid fromcompound 0607-84 (100 mg, 0.358 mmol), 0107-115 (120 mg, 0.394 mmol),CuI (7 mg, 0.0358 mmol), t-BuONa (34 mg, 0.0358 mmol), neocuporine (8mg, 0.0358 mmol) and DMF (3 mL) using a procedure similar to thatdescribed for compound 84 (Example 59): m.p. 81-86° C. LC-MS: 457.2[M+1]⁺. ¹H-NMR (DMSO-d⁶): δ 0.77 (s, 9H), 2.16 (s, 8H), 2.70 (m, 2H),3.48 (s, 2H), 4.18 (m, 2H), 6.00 (s, 2H), 6.28 (m, 2H), 6.64 (s, 1H),6.80 (m, 1H), 6.97 (s, 1H), 7.68 (m, 1H).

Example 65 Preparation of2-(6-ethylbenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 85) Step 65a. 5-Ethyl-6-iodobenzo[d][1,3]dioxole (Compound0107-85)

t-BuOK (7.77 g, 69.3 mmol) was added portions to a suspension ofcompound methyltriphenylphosphonium iodide (28.0 g, 68.3 mmol) in dryTHF (250 mL) over 10 min at 0° C. The resulting yellow suspension wasstirred for 20 min at this temperature. A solution of piperonal (8.0 g,53.3 mmol) in dry THF (25 mL) was added dropwise to the above suspensionand the mixture was stirred for 1 h at 0° C. The reaction mixture wasconcentrated and the residue was purified by column chromatograph(petroleum ether) to provide compound 5-vinylbenzo[d][1,3]dioxole (7.4g, 94%) as colorless liquid. ¹H-NMR (DMSO-d⁶): δ 5.09 (d, 1H, J=11.2Hz), 5.68 (d, 1H, J=18 Hz), 6.00 (s, 2H), 6.63 (1, 1H, J₁=11.2 Hz, J₂=18Hz), 6.85 (m, 2H), 7.11 (s, 1H).

A mixture of 5-vinylbenzo[d][1,3]dioxole (6.0 g, 40.5 mmol) and 10% Pd/C(840 mg) in MeOH (50 mL) was hydrogenated for 8 h at 10 atm. Then Pd/Cwas filtered and the MeOH was removed to give compound5-ethylbenzo[d][1,3]dioxole (3.0 g, 50%) as colorless liquid. ¹H-NMR(DMSO-d⁶): δ 1.11 (t, 3H, J=7.2 Hz), 2.50 (q, 2H, J₁=7.2 Hz, J₂=16 Hz),5.93 (s, 2H), 6.64 (d, 1H, J=8 Hz), 6.77 (m, 2H).

A mixture of compound 5-ethylbenzo[d][1,3]dioxole (3.0 g, 20 mmol), NIS(6.0 g, 22 mmol) and TFA (2.3 g, 20 mmol) in 30 mL of CH₃CN was stirredfor 5 hours at room temperature. Saturated Na₂S₂O₃ solution was thenadded dropwise to the mixture until the color was faded. CH₃CN wasevaporated in vacuo and the mixture was extracted with ethyl acetate (20mL×2). The organic phase was dried and concentrated to obtain the titlecompound 0107-85 (5.3 g, 96%) as a yellow solid. GC-MS 276 [M+1]⁺, ¹HNMR (DMSO-d⁶): δ 1.06 (t, 3H, J=7.6 Hz), 2.57 (q, 2H, J=7.6 Hz), 6.00(s, 2H), 6.93 (s, 1H), 7.30 (s, 1H).

Step 65b.2-(6-Ethylbenzo[d][1,3]dioxol-5-ylthio)-1-(2-(neopentylamino)ethyl)-1H-imidazo[4,5-c]pyridin-4-amine(Compound 85)

The title compound 85 was prepared (40 mg, 26%) as a yellow solid fromcompound 0607-84 (100 mg, 0.358 mmol), 0107-85 (127 mg, 0.466 mmol),neocuproine (8 mg, 0.0358 mmol), CuI (7 mg, 0.036 mmol), and t-BuONa (52mg, 0.537 mmol) in anhydrous DMF (5 ml) using a procedure similar tothat described for compound 84 (Example 59): m.p. 145˜147° C., LCMS: 428[M+1]⁺¹H NMR (DMSO-d⁶): δ 0.79 (s, 9H), 1.14 (t, 3H, J=7.2 Hz), 1.65(bs, 1H), 2.18 (s, 2H), 2.75 (t, 2H, J=5.6 Hz), 2.78 (q, 2H, J=7.6 Hz),4.23 (t, 2H, J=6.0 Hz), 6.01 (s, 2H), 6.21 (s, 2H), 6.72 (s, 1H), 6.82(d, 1H, J=5.6 Hz), 6.96 (s, 1H), 7.69 (d, 1H, J=5.2 Hz).

Biological Assays:

As stated hereinbefore the derivatives defined in the present inventionpossess anti-proliferation activity. These properties may be assessed,for example, using one or more of the procedures set out below:

(a) an In Vitro Assay which Determines the Ability of a Test Compound toInhibit Hsp90 Chaperone Activity.

The Hsp90 chaperone assay was performed to measure the ability of HSP90protein to refold the heat-denatured luciferase protein. HSP90 was firstincubated with different concentrations of test compounds indenaturation buffer (25 mM Tris, pH7.5, 8 mM MgSO₄, 0.01% bovine gammaglobulin and 10% glycerol) at room temperature for 30 min. Luciferaseprotein was added to denaturation mix and incubated at 50° C. for 8 min.The final concentration of HSP90 and luciferase in denaturation mixturewere 0.375 μM and 0.125 μM respectively. A 5 μl sample of the denaturedmix was diluted into 25 μl of renaturation buffer (25 mM Tris, pH7.5, 8mM MgSO₄, 0.01% bovine gamma globulin and 10% glycerol, 0.5 mM ATP, 2 mMDTT, 5 mM KCl, 0.3 μM HSP70 and 0.15 μM HSP40). The renaturationreaction was incubated at room temperature for 150 min, followed bydilution of 10 μl of the renatured sample into 90 μl of luciferinreagent (Luclite, PerkinElmer Life Science). The mixture was incubatedat dark for 5 min before reading the luminescence signal on a TopCountplate reader (PerkinElmer Life Science).

(b) HSP90 Competition Binding (Fluorescence Polarization) Assay.

A fluorescein isothiocyanate (FITC) labeled GM was purchase fromInvivoGen (ant-fgl-1). The interaction between HSP90 and labeled GMforms the basis for the fluorescence polarization assay. A free andfast-tumbling FITC labeled GM emits random light with respect to theplane of polarization plane of excited light, resulting in a lowerpolarization degree (mP) value. When GM is bound to HSP90, the complextumble slower and the emitted light is polarized, resulting in a highermP value. This competition binding assay was performed in 96-well plateand with each assay contained 10 and 50 nM of labeled GM and purifiedHSP90 protein (Assay Design, SPP-776F) respectively. The assay buffercontained 20 mM HEPES (pH 7.3), 50 mM KCl, 1 mM DTT, 50 mM MgCl₂, 20 mMNa₂MoO4, 0.01% NP40 with 0.1 mg/ml bovine gamma-globulin. Compounds arediluted in DMSO and added to the final assay before labeled GM withconcentration range from 20 uM to 2 nM. mP value was determined byBioTek Synergy II with background subtraction after 24 hours ofincubation at 4° C.

The following TABLE B lists compounds representative of the inventionand their activity in HSP90 assays. In these assays, the followinggrading was used: I≧10 μM, 10 μM>II>1 μM, 1 μM>III>0.1 μM, and IV≦0.1 μMfor IC₅₀.

TABLE B Compound HSP90 Chaperone HSP90 Binding No. (IC₅₀) (IC₅₀) 1 IIIIII 2 III III 3 III IV 4 III 7 III 9 I 11 I I 12 II III 13 II II 14 IIII 15 I 16 I 17 I I 18 II 19 II II 21 I 22 II 23 III 24 II 25 III 26 II27 II 28 III 29 II 30 III 32 III 33 III 34 III IV 37 IV 40 III 42 III 44III 46 III 48 II 50 III 51 II 52 III 53 II 54 II 56 III 58 III 60 III 61III 62 III 64 II 66 III 68 III 70 III 72 III 74 III 76 III 77 III 78 II79 III 84 III 85 III 86 II 87 III 89 III 101 I 111 IV 113 III 115 I

A representative compound of the invention has been shown to have afavorable pharmacological kinetic (PK) profile and a high degree ofbrain penetration following systemic administration. In a tMAO model(Dellovade, T. Annu. Rev. Neurosci., 2006, 29, 539-563), a single ivdose of 10 mg/kg of the compound in rat has been demonstrated tosignificantly reduce total brain infarct volume by approximately 33% at4 hours post-tMCAO.

The patent and scientific literature referred to herein establishes theknowledge that is available to those with skill in the art. All UnitedStates patents and published or unpublished United States patentapplications cited herein are incorporated by reference. All publishedforeign patents and patent applications cited herein are herebyincorporated by reference. All other published references, documents,manuscripts and scientific literature cited herein are herebyincorporated by reference.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1.-24. (canceled)
 25. A compound represented by the formula

wherein X is chloro and Y is hydrogen; or X is chloro or amino and Y isneopentyl.
 26. The compound of claim 25 represented by the formula


27. The compound of claim 25 represented by the formula


28. The compound of claim 25 represented by the formula